Clinical Pharmacokinetics

Published by Springer Verlag
Online ISSN: 1179-1926
Print ISSN: 0312-5963
Objective: To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. Methods: Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after application of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 microg/L. Results: At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (C(max)) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean +/- SD) 1.20 +/- 0.41 microg/L (n = 10) and 17.0 +/- 6.1 microg. h/L (n = 10), respectively, and occurred on day 15. The single highest C(max) was 1.91 microg/L. At standard application rates in patients with acne vulgaris, the maximum average C(max) and AUC values of tazarotenic acid were 0.10 +/- 0.06 microg/L (n = 8) and 1.54 +/- 1.01 microg. h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were (mean +/- SD) 1.75 +/- 0.53 microg/L (n = 16) and 23.8 +/- 7.0 microg. h/L (n = 16), respectively, and occurred on day 22. The single highest C(max) was 3.43 microg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were 0.236 +/- 0.255 microg/L (n = 8) and 2.44 +/- 1.38 microg. h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. Conclusions: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 microg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 microg/L.
Linagliptin (BI 1356) is a highly specific inhibitor of dipeptidyl peptidase (DPP)-4, which is currently in phase III clinical development for the treatment of type 2 diabetes mellitus. Linagliptin exhibits nonlinear pharmacokinetics after oral administration, which are mainly related to concentration-dependent binding of linagliptin to its target, DPP-4. The objectives of the study were to investigate the pharmacokinetics and pharmacodynamics after intravenous administration of linagliptin and to determine its absolute bioavailability (F). This was a single rising-dose, randomized, four-group, placebo-controlled, single-blind (within dose groups) study. Thirty-six healthy men aged 18-50 years were enrolled and randomized into four sequential treatment groups. Group 1 received linagliptin 0.5 mg intravenously, group 2 received 2.5 mg intravenously and group 4 received 10 mg intravenously. In group 3, subjects underwent a two-way randomized crossover, receiving 5 mg intravenously and a 10 mg oral tablet. Linagliptin concentrations in plasma and urine, as well as plasma DPP-4 activity, were determined by validated assays. Noncompartmental analysis and population pharmacokinetic modelling were performed. Linagliptin showed nonlinear pharmacokinetics after intravenous infusion of 0.5-10 mg, with a less than dose-proportional increase in exposure. Noncompartmental parameters were calculated on the basis of total (i.e. bound and unbound) plasma concentrations. The total clearance value was low and increased with dose from 2.51 to 14.3 L/h. The apparent steady-state volume of distribution (V(ss)) increased with dose from 380 to 1540 L. Renal excretion of the unchanged parent compound increased with increasing plasma concentrations from 2.72% in the 0.5 mg dose group to 23.0% in the 10 mg dose group. The terminal elimination half-life was comparable across dose groups (126-139 hours). Because of the nonlinear pharmacokinetics, the standard approach of comparing the area under the plasma concentration-time curve (AUC) after oral administration with the AUC after intravenous administration led to dose-dependent estimates of the absolute bioavailability. Therefore, a population pharmacokinetic model was developed, accounting for the concentration-dependent protein binding of linagliptin to its target enzyme, DPP-4. The model-derived estimates of the V(ss) and clearance of linagliptin not bound to DPP-4 were 402.2 L and 26.9 L/h, respectively. The absolute bioavailability was estimated to be about 30% for the linagliptin 10 mg tablet. The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.
Methods: The predictive value of the allometric equation, clearance (CL) is equal to 0.071 × bodyweight in kg0.78, which was developed from rats, children and adults, and the predictive value of a fixed exponent allometric model derived from the basal metabolic rate, CL is equal to CL standardized to a 70 kg adult × (bodyweight in kg standardized to a 70 kg adult)0.75, were evaluated across five independent patient groups including (i) 25 (pre)term neonates with a postmenstrual age of 27–43 weeks; (ii) 22 postoperative infants aged 4–18 months; (iii) 12 toddlers aged 1–3 years; (iv) 14 adolescents aged 10–20 years; and (v) 26 critically ill adults sedated long term. The median percentage error of the predictions was calculated using the equation %error = (CLallometric − CLi)/CLi × 100, where CLallometric is the predicted propofol clearance from the allometric equations for each individual and CLi is the individual-predicted (post hoc) propofol clearance value derived from published population pharmacokinetic models.
Background and objectives: PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic exposure, across trials and patient populations. Methods: A total of 6,107 samples of PF-00610355 plasma concentration, collected in 264 subjects from eight studies in healthy volunteers, asthma, and COPD patients, were analyzed using non-linear mixed-effects models. Model-based mean (95 % CI) exposure profiles for a range of PF-00610355 doses in COPD patients were simulated. Results: PF-00610355 exposure profiles were described by a three-compartment disposition model with first-order absorption through a transit compartment. Patient status, inhalation device, and demographic factors were found to influence systemic drug exposure. Relative fine particle dose had a minor effect, whereas no effect of baseline lung function on the systemic exposure was found. An implicit method to address pharmacokinetic variability between occasions of drug intake yielded similar results as the established explicit method, yet in a much more efficient way. Conclusion: The estimated systemic pre-dose and maximum PF-00610355 plasma concentration was 23 and 38 % in COPD patients compared to healthy volunteers, respectively. The analysis illustrated the value of an integrated pharmacokinetic analysis to address specific challenges in the clinical development of long-/ultra-long-acting β2-agonists and inhaled compounds in general, both in relation to selecting a safe starting dose in patients, but also in understanding exposure and systemic safety information across different patient populations and different inhalation devices/formulations.
NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population. NXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CL(CR)). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CL(CR) or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfillment criteria and parsimony. Pharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34-92 years with varying degrees of renal impairment (estimated CL(CR) 20-143 mL/min). The final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CL(CR) and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CL(CR) of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CL(CR) (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min. The results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.
To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant. An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods. Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced. When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required. The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.
Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza.
Pharmacokinetic profiles of the 1,4-substituted benzodiazepines are defined by their absorption, distribution, metabolism, and excretion characteristics. An ability to cross the blood-brain barrier and the onset of pharmacological activity have been associated with the physiochemical properties of the benzodiazepines. In addition, drug concentrations in the CSF correlate with the unbound drug concentrations in blood or plasma. Duration of pharmacological activity of the benzodiazepines in humans is associated with the affinity of these compounds for the benzodiazepine receptors in human brain. Therefore, benzodiazepines with high affinity for the benzodiazepine receptor sites in human brain tend to exhibit prolonged half-lives of elimination from the CSF which correlate with the prolonged duration of clinical and pharmacological effects and lower therapeutic doses of these drugs in vivo.
Recent international guidelines on the detection, clinical assessment and management of patients with hypertension have highlighted a number of themes that should be incorporated into routine clinical practice. First, although antihypertensive therapy is having a major impact on reducing the incidence of coronary heart disease, cerebrovascular disease and heart failure, community surveys show that most hypertensive patients remain untreated or have suboptimal blood pressure control. Second, the guidelines have emphasised the importance of making an overall assessment of individual patients to gauge their absolute risk of a cardiovascular event; risk factors include not only blood pressure but also target organ damage, the presence of coexisting symptomatic vascular disease and the number of associated cardiovascular risk factors. Patients at the highest risk, especially those with diabetes, the elderly and patients with target organ damage, merit vigorous antihypertensive therapy, and such patients often require treatment with more than one drug to achieve target levels of blood pressure (<135/80mm Hg). An additional important theme in recent guidelines has been a move towards using lower dosages and therapies that provide 24-hour blood pressure control with once-daily administration. Since diuretics have been reaffirmed as evidence-based first-line therapy in a broad spectrum of patients with hypertension, especially the elderly, a new lower dosage sustained release formulation of indapamide has been developed (indapamide SR 1.5mg). Recent multicentre European clinical trials have defined the efficacy and tolerability of indapamide SR 1.5mg, both relative to other antihypertensive drugs and in key subgroups of patients. Indapamide SR 1.5mg has an antihypertensive effect, maintained throughout the 24-hour administration interval, equivalent to that of immediate release indapamide 2.5mg, but the new formulation has even less effect on circulating K+ levels. Indapamide SR 1.5mg is at least as effective as amlodipine or hydrochlorothiazide. In patients with left ventricular hypertrophy (LVH), a comparative study of indapamide SR 1.5mg and enalapril (the LIVE study) used a rigorous unique study design with blinded reading of echocardiograms to show that after 1 year the ACE inhibitor had no significant effect on LVH regression, whereas indapamide SR 1.5mg produced significant reductions in left ventricular mass index. Diuretic-based therapy for hypertension has been reaffirmed in international guidelines as effective first-line therapy, especially in the elderly and patients with LVH. Indapamide SR 1.5mg shows an improved efficacy-tolerability profile, with impressive 24-hour effects on blood pressure, important ancillary properties with regard to LVH and cardiovascular protection.
In accordance with international guidelines recommending the use of low doses of antihypertensive agents, a new formulation of indapamide — indapamide sustained release (SR) — has been developed. Indapamide has been used worldwide for many years as an immediate release (IR) formulation at a dose of 2.5mg. The IR formulation leads to plasma peaks of indapamide immediately after administration of the tablet. These peaks are responsible for possible unfavourable electrolyte or metabolic effects relating to indapamide blood concentrations. The SR formulation, by eliminating plasma peaks, allows a smoothing of the pharmacokinetic profile of indapamide. This new galenic formulation is based on a hydrophilic matrix tablet composed of a cellulose derivative, methylhydroxypropylcellulose (MHPC), and a binder, polyvinylpyrrolidone (povidone). The originality of the matrix lies in the percentages of MHPC and povidone, which permit a linear release in vitro of indapamide. After optimisation, the chosen ratio of these 2 constituents allowed the release of more than 70% of the dosage over 16 hours in a very reproducible manner. The 2 tested formulations (SR and IR) have the same bioavailability; however, the main pharmacokinetic parameters of the new SR 1.5mg formulation, calculated after single and repeated administration, show a profile typical of an SR formulation, i.e. a lower maximum concentration (Cmax), a longer time to Cmax, and the same minimum concentration as the IR formulation. This new SR formulation, which allows a reduction in the daily dose of indapamide from 2.5 to 1.5mg, leads to an improvement in its efficacy/tolerability ratio, thereby meeting the recommendations of the international guidelines for the treatment of essential hypertension.
Plasma concentrations of carbamazepine were monitored in 9 pregnant epileptic patients treated with the drug alone at constant doses during pregnancy and for at least 3 months after delivery. In addition, plasma concentrations of the metabolite, carbamazepine 10,11-epoxide were measured in 6 of the 9 patients. Plasma carbamazepine concentrations were fairly stable during pregnancy, and carbamazepine relative plasma clearances were significantly higher in weeks 4 to 24 than in weeks 25 to 32. After the end of the second trimester, there were no variations in plasma carbamazepine 10,11-epoxide concentrations and carbamazepine 10,11-epoxide:carbamazepine ratios. Both parameters were significantly higher in weeks 4 to 24 than in weeks 25 to 32 of pregnancy.
Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 µmol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown. The mean plasma half-life of unchanged epoxide was 6.1 hours with a mean volume of distribution of 0.74 L/kg. Six patients with trigeminal neuralgia had their optimal carbamazepine dose replaced with carbamazepine-10,11-epoxide for 3 to 6 days. The study was single-blind and placebo controlled. When carbamazepine and the epoxide were given in similar doses, the pain control was comparable. The results show that during carbamazepine therapy, the contribution of the epoxide to the effect is considerable. No side effect was seen during the epoxide therapy. Further studies on the effect of carbamazepine-10,11-epoxide administration in epilepsy are indicated.
Total and free plasma concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) were determined in 39 children (aged 3 to 10 years) and 79 adults (aged 15 to 65 years) receiving long term treatment with CBZ alone or in combination with phenobarbitone (PB). Compared with the corresponding age groups treated with CBZ alone, adults and children receiving PB co-medication showed lower total and free CBZ concentrations, similar CBZ-E concentrations and higher CBZ-E/CBZ ratios. Among patients on CBZ alone, children had at any given dose lower total and free CBZ and CBZ-E concentrations than adults. Lower CBZ levels in children than in adults were also found among patients receiving phenobarbitone in combination. CBZ-E/CBZ ratios did not differ significantly between children and adults. These data provide evidence that children show an elevated free CBZ clearance with a metabolic pattern different from that observed during phenobarbitone induction.
The single dose pharmacokinetics of 4 commercially available 100mg oral aspirin formulations were studied in 6 healthy men and 6 healthy women. Two of the formulations were rapid release (‘Cardiprin’ 100, ‘Platelin’) and the other 2 were enteric coated formulations (‘Astrix’ 100, ‘Cartia’). There were marked differences in the plasma concentration-time profiles between the rapid release and the enteric coated formulations. There were no significant differences (p > 0.05) in the mean time to achieve maximum aspirin concentrations between ‘Cardiprin’ 100 (0.48h) and ‘Platelin’ (0.35h), but this was significantly prolonged (p < 0.001) for ‘Astrix’ 100 (3.73h) and even more prolonged for ‘Cartia’ (6.84h). Similar between-formulation differences were seen in the areas under the plasma concentration-time curves, for which the rank order was ‘Cardiprin’ 100 (1.60 mg/L · h) = ‘Platelin’ (1.54 mg/L · h) > ‘Astrix’ 100 (0.73 mg/L · h) > ‘Cartia’ (0.56 mg/L · h). For ‘Cardiprin’ 100, ‘Platelin’ and ‘Astrix’ 100 plasma aspirin concentrations were below 5 µg/L by 7h after ingestion, whereas for ‘Cartia’ aspirin was detectable for up to 16h, giving the appearance of sustained release. The enteric coated formulations produced the greatest variability in the plasma aspirin concentration vs time profiles. The urinary recovery of salicylate was greater than 80% of the administered dose for all 4 formulations. The clinical significance of the marked pharmacokinetic differences observed with these 4 low-dose aspirin formulations is not known.
Fifteen depressed elderly patients (14 female, 1 male; mean age 85 years) received a single oral dose of amitriptyline. The concentration of amitriptyline plus nortriptyline in a blood sample taken 24 hours later was used to predict by means of a nomogram the amitriptyline dosage required for each patient. Each dose was selected to produce steady-state amitriptyline plus nortriptyline concentrations close to 140 μg/L. The daily dosage ranged from 20 to 100mg (mean 62mg). Patients received the individually calculated dose each night, and weekly blood samples were obtained for drug analysis. At 2 weeks, mean amitriptyline plus nortriptyline concentrations were 118 ± 21 μg/L. Eight of the patients were studied for a further 2 weeks and the mean amitriptyline plus nortriptyline concentration was then 111 ± 19 Mg/L. The dose prediction test is easy to use and ensures each patient receives an adequate but safer dose of amitriptyline than might otherwise be prescribed routinely.
Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and methotrexate. A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated.
Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics. The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters. Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling. The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001). The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated.
ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.
In microdose studies, the pharmacokinetic profile of a drug in blood after administration of a dose up to 100 μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending pharmacokinetic analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the pharmacokinetic profile of the model drug verapamil in plasma and brain of humans. In order to assess pharmacokinetic dose linearity of verapamil, data were acquired and compared after administration of an intravenous microdose and after an intravenous microdose administered concomitantly with an oral therapeutic dose. Six healthy male subjects received an intravenous microdose [0.05 mg] (period 1) and an intravenous microdose administered concomitantly with an oral therapeutic dose [80 mg] of verapamil (period 2) in a randomized, crossover, two-period study design. The intravenous dose was a mixture of (R/S)-[14C]verapamil and (R)-[11C]verapamil and the oral dose was unlabelled racaemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma pharmacokinetics of (R)- and (S)-verapamil were determined with AMS. PET data were analysed by pharmacokinetic modelling to estimate the rate constants for transfer (k) of radioactivity across the blood-brain barrier. Most pharmacokinetic parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (influx rate constant [K(1)] = 0.030 ± 0.003 and 0.031 ± 0.005 mL/mL/min and efflux rate constant [k(2)] = 0.099 ± 0.006 and 0.095 ± 0.008 min-1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for nonlinear pharmacokinetics for the (R)-enantiomer. On the other hand, all pharmacokinetic parameters (except for the terminal elimination half-life [t1/2;)]) differed significantly between the (R)- and (S)-enantiomers for both periods. The maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC(24)) and AUC from time zero to infinity (AUC(∞)) were higher and the total clearance (CL), volume of distribution (V(d)) and volume of distribution at steady state (V(ss)) were lower for the (R)- than for the (S)-enantiomer. Conclusion: Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.
N-Acetylcysteine is useful as a mucolytic agent for treatment of chronic bronchitis and other pulmonary diseases complicated by the production of viscous mucus. It is also used as an antidote to paracetamol (acetaminophen) poisoning and found to be effective for the prevention of car-diotoxicity by doxorubicin and hae norrhagic cystitis from oxazaphosphorines. After an oral dose of N-acetylcysteine 200 to 400mg the peak plasma concentration of 0.35 to 4 mg/L is achieved within 1 to 2 hours. Although the data are conflicting, it appears that the administration of charcoal may interfere with drug absorption, with up to 96% of the drug adsorbed on to the charcoal. Information on absorption in the presence of food or other drugs is not available. The volume of distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant, reaching approximately 50% 4 hours after the dose. Pharmacokinetic information is not available as to whether or not N-acetylcysteine crosses the blood-brain barrier or placenta, or into breast milk. Renal clearance has been reponed as 0.190 to 0.211 L/h/ke and approximately 70% of the total body clearance is nonrenal. Following oral administration, reduced /V-acetyl-cysteine has a terminal half-life of 6.25h. Little is known of the metabolism of this agent, although it is believed to be rapidly metabolised and incorporated on to proteins. The major excretory product is inorganic sulphate. Frequently reported side effects are nausea, vomiting and diarrhoea. Biochemical and hae-matological adverse effects are observed but are not clinically relevant. Drug interactions of clinical significance have been observed with paracetamol, glutathione and anticancer agents.
Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66 %. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.
Background: Human mass balance studies and the assessment of absolute oral bioavailability (F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. Objectives: The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CLR) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Methods: Six healthy male subjects received 20 mg [(12)C/(14)C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [(13)C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [(12)C]tofogliflozin in plasma and urine and [(13)C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. Results: The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state (V(ss)) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL(R) of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma (f(u)) (eGFR × f(u) 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CLR contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CLR by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. Conclusions: These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V(ss. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion.
The pharmacokinetics of omeprazole and its metabolites following single doses were studied in 8 patients with liver cirrhosis. Each patient participated in 2 experiments in which [14C]omeprazole was administered either intravenously (20mg) or in an oral solution (40mg) in a randomised crossover design. Plasma concentrations of omeprazole and 2 of its identified metabolites, as well as total radioactivity were followed for 24h; urinary excretion was followed for 96h. The mean elimination half-life of omeprazole in the patients with cirrhosis was 2.8h and the mean total plasma clearance was 67 ml/min (4.02 L/h); corresponding values from separate studies in young healthy volunteers were 0.7h and 594 ml/min (35.64 L/h). The mean systemic availability was nearly 100% in the patients with cirrhosis whereas the previously reported value in young volunteers was only 56%. Almost 80% of a given dose was excreted as urinary metabolites in both patients and young volunteers. It is concluded that, as the hepatic clearance of omeprazole was substantially reduced in these patients, the dose of omeprazole needed for a certain degree of acid suppression is lower in patients with liver cirrhosis.
The dopamine agonist rotigotine has been formulated in a silicone-based transdermal system for once-daily administration. The objective of the present study was to characterise the mass balance of rotigotine in humans after administration of a single transdermal patch containing radiolabelled [(14)C]rotigotine and to quantify the pharmacokinetic profiles of total radioactivity and the corresponding rotigotine plasma concentrations. In a phase I trial, six healthy male Caucasian subjects were administered a single 10 cm(2) patch containing 4.485mg of unlabelled and 0.015mg of [(14)C]-labelled rotigotine (total radioactivity 0.09 MBq per patch) with a patch-on period of 24 hours. Radioactivity was determined by liquid scintillation counting in unused patches, used patches, skin wash samples after 24 hours, plasma, urine and faeces samples up to 96 hours and skin stripping samples at 96 hours post-application. Unconjugated rotigotine in plasma samples was determined by liquid chromatography with tandem mass spectrometry. Plasma samples were taken predose and 2, 4, 6, 8, 12, 24, 48, 72 and 96 hours after patch application. The rotigotine transdermal patch was well tolerated, and all subjects completed the trial. A total of 94.6% of the administered dose was recovered within 96 hours after patch application inclusive of the residual amounts in the patch. Within 24 hours, 51% of the total radioactivity was delivered to the human body system and 46.1% was systemically absorbed. Total radioactivity recovered in urine and faeces was 30.4% and 10.2%, respectively, of the radioactivity applied (corresponding to 65.8% and 21.8% of the dose absorbed, respectively). The mass balance of rotigotine within 96 hours after transdermal delivery of rotigotine via a 10 cm(2) [(14)C]rotigotine patch with a total drug content of 4.5mg (corresponding to the nominal dose of 2mg/24 hours for the marketed rotigotine transdermal system) has been 95% explained. The systemic absorption was 46.1% of the administered dose, the majority of which was cleared from the body via urine and faeces within 96 hours after patch application.
Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. To investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion. This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation. In a randomised crossover study, six healthy male subjects (age range 19-40 years) received single doses of 6.9 mg (oral administration) and 0.64 mg (intravenous administration) of [14C]ciclesonide, separated by a washout period of at least 14 days. Total radioactivity was determined in whole blood, plasma, urine and faeces. Serum concentrations of ciclesonide and its major metabolite, the pharmacologically active desisobutyryl-ciclesonide (des-CIC), were determined in serum by high-performance liquid chromatography with tandem mass spectrometry detection. After a 10-minute intravenous infusion, the mean half-life for total radioactivity was 45.2 hours. Elimination of des-CIC was fast with a mean elimination half-life of 3.5 hours. After oral administration, the mean half-life for total radioactivity was 27.5 hours. On the basis of a comparison of dose-normalised areas under the curve of total plasma radioactivity versus time, 24.5% of orally administered [14C]ciclesonide was absorbed. The parent compound ciclesonide was not detected in any of the serum samples after oral administration; serum concentrations of des-CIC were mostly near or below the lower limit of quantification. Thus, systemic bioavailability for des-CIC is <1% and the absolute bioavailability of ciclesonide is even less than this. [14C]Ciclesonide showed no retention in red blood cells. The mean cumulative excretion of total radioactivity was almost complete by 120 hours after oral and intravenous administration. Faecal excretion was the predominant route of excretion for total radioactivity after both routes of administration. Single oral and intravenous administration of ciclesonide was well tolerated. Because of an almost complete first-pass metabolism, ciclesonide is undetectable in serum after oral administration. Thus, any ciclesonide swallowed after oral inhalation does not contribute to systemically available ciclesonide or to its active metabolite. Drug-related metabolites are excreted mainly via the faeces, and overall recovery of administered radioactivity is virtually complete after an extended sample collection period.
Carboplatin shares some of the therapeutic advantages of cisplatin, but without a significant incidence of the dose-limiting neurotoxicity and nephrotoxicity which is experienced with cisplatin. However, its use is associated with dose-limiting bone marrow suppression. Carboplatin is present in the blood as 3 distinct species. These are total platinum and 2 unbound species, carboplatin itself and a decarboxylated platinum-containing degradation product. The 2 main methods used to assay the unbound species are flameless atomic absorption spectrophotometry and high performance liquid chromatography. The first of these methods assays both unbound platinum species, the second is specific for carboplatin. Both unbound species have similar pharmacokinetic profiles for the first 12 hours post-dose. Carboplatin appears to have a linear pharmacokinetic profile over the doses used clinically and does not interact significantly with drugs that are used commonly in combination chemotherapy. The pharmacokinetics of carboplatin are adequately described by an open 2-compartment model with elimination from the central compartment. Its clearance is proportional to the glomerular filtration rate and the volume of distribution of the central compartment appears to correlate with extracellular fluid volume. The elimination half-life varies with renal function and is typically between 2 and 6 hours in patients with a normal glomerular filtration rate and may be as long as 18 hours in patients with impaired renal function. Relationships between systemic exposure to carboplatin, described as the area under the concentration-time curve (AUC), and both toxicity and response have been described. For toxicity the strongest evidence exists for a relationship between AUC and thrombocytopenia. To a lesser extent the relationship between AUC and neutropenia has also been described. Patients already treated with platinum analogues have been shown to develop a greater degree of myelosuppression from any given AUC. In addition, some evidence suggests a relationship between the shape of the concentration-time curve and myelotoxicity, where constant infusions appear less likely to cause myelosuppression on a mg/m2 dose administration basis. The relationship between AUC and response rate is not as clear, this may be related to the lack of studies describing both the dose and AUC of carboplatin. There appears to be a more clearly defined AUC-response relationship for ovarian cancer than for other malignancies, with an AUC of between 5 and 7 mg/ml · min being associated with the maximal response rate [located at the plateau on an AUC-response curve]. However, new data suggest that higher AUCs may lead to greater response rates. Data from testicular cancer also strongly supports an AUC-response relationship with an increased number of treatment failures with carboplatin AUCs < 5 to 6 mg/ml · min. Given the AUC-effect relationships described above a number of studies have been performed to develop models to describe the relationship between both dose and AUC and dose and platelet nadir. In adults, perhaps the most common method is that of Calvert which describes the relationship between dose and AUC. Paediatric formulas have also been described. More recently a number of limited sampling strategies have been proposed as well as Bayesian dose individualisation techniques.
Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics. Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods. Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of distribution in the Uf Pt model, and both IP and serum protein concentrations for the clearance from the central compartment in the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described. The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.
Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.
17alpha-Ethinylestradiol (EE) is widely used as the estrogenic component of oral contraceptives (OC). In vitro and in vivo metabolism studies indicate that EE is extensively metabolised, primarily via intestinal sulfation and hepatic oxidation, glucuronidation and sulfation. Cytochrome P450 (CYP)3A4-mediated EE 2-hydroxylation is the major pathway of oxidative metabolism of EE. For some time it has been known that inducers of drug-metabolising enzymes (such as the CYP3A4 inducer rifampicin [rifampin]) can lead to breakthrough bleeding and contraceptive failure. Conversely, inhibitors of drug-metabolising enzymes can give rise to elevated EE plasma concentrations and increased risks of vascular disease and hypertension. In vitro studies have also shown that EE inhibits a number of human CYP enzymes, such as CYP2C19, CYP3A4 and CYP2B6. Consequently, there are numerous reports in the literature describing EE-containing OC formulations as perpetrators of pharmacokinetic drug interactions. Because EE may participate in multiple pharmacokinetic drug interactions as either a victim or perpetrator, pharmaceutical companies routinely conduct clinical drug interaction studies with EE-containing OCs when evaluating new chemical entities in development. It is therefore critical to understand the mechanisms underlying these drug interactions. Such an understanding can enable the interpretation of clinical data and lead to a greater appreciation of the profile of the drug by physicians, clinicians and regulators. This article summarises what is known of the drug-metabolising enzymes and transporters governing the metabolism, disposition and excretion of EE. An effort is made to relate this information to known clinical drug-drug interactions. The inhibition and induction of drug-metabolising enzymes by EE is also reviewed.
Due in the main to a genetically determined difference in the activity of the liver N-acelyltransferase, a number of primary amine drugs or drug metabolites such as dapsone, isoniazid, hydrallazine, phenelzine, procainamide, sulphadimidine, sulphapyridine and nitrazepam are subject to a bimodal acetylation in man. The population ratio of rapid versus slow acetylators varies widely between ethnic groups throughout the world, apparently being highest in those of an Eastern Asian origin and lowest in Egypt and some Western European countries. With some exceptions, the general clinical consequences of these differences in acetylator phenotype are, if any, that when patients are given a standard dose of the drugs mentioned, the slow acetylators are those who develop most adverse reactions while the rapid acetylators seem more prone to show an inadequate or lack of response to the standard dose. The rationale behind dose adjustments based upon acetylator phenotyping is discussed, and it is tentatively concluded that more precise knowledge about the acetylator phenotype of the therapy. However, the possibility that a variety of pathophysiological factors and the concomitant therapy. However, the possibility that a variety of pathophysiological factors and the concomitant use of other drugs may interfere with acetylator phenotyping has to be considered, as well as some recent evidence that the acetylator phenotype may in itself represent a determinant for the development of certain diseases, like systemic lupus erythematosus and renal failure.
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency. Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data. In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10). Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.
Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful anticancer agents, and is also widely used for its immunosuppressive properties. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard. Sensitive and specific methods are now available for the measurement of cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated. Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Longer term complications of cyclophosphamide therapy include infertility and an increased incidence of second malignancies. Cellular sensitivity to cyclophosphamide is a function of cellular thiol concentration, metabolism by aldehyde dehydrogenases to form inactive metabolites, and the ability of DNA to repair alkylated nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.
The following summarises the contents of both this review and its predecessor in this journal (Iisalo, 1977). The two reviews should be read in conjunction with each other. Digoxin is absorbed mostly from the proximal part of the small intestine. About 67% is absorbed from tablets, 80% from elixir and up to 100% from encapsulated elixir. Protein binding of digoxin and its metabolites is low and of little clinical significance. Digoxin is widely distributed throughout body tissues and has a high apparent volume of distribution (about 6L/kg). Although most of the digoxin in the body is in skeletal muscle it is found in highest concentrations in the heart, kidneys and brain. The apparent volume of distribution is reduced in patients with renal impairment and in the elderly. Plasma digoxin concentrations do not closely reflect myocardial whole tissue concentrations. The half-time of elimination in healthy subjects averages 40 hours. In most patients, more than 80% of digoxin is excreted unchanged in the urine but in about 12% of patients between 20% and 55% is excreted as metabolites, mostly dihydrodigoxin, which is relatively inactive. In a few subjects other, more active, metabolites may be found in the urine. Renal elimination is mainly by glomerular filtration but some passive tubular reabsorption and active secretion occur. The relationships between plasma digoxin concentrations and its pharmacodynamic or therapeutic effects are not clear. However, plasma digoxin concentrations may relate well to the slowing of ventricular rate from pre-treatment values in atrial fibrillation but not to resting ventricular rates. In cardiac failure in sinus rhythm, plasma digoxin concentrations may relate well to the inotropic effect of the drug but theoretical tissue digoxin concentrations may be more closely related. Digoxin passes across the placenta and into breast milk but not in sufficient quantities to prove harmful to the fetus or neonate. In renal impairment, the half-time of digoxin is prolonged and its apparent volume of distribution reduced. The pharmacokinetics of digoxin in different states of thyroid function are complex and do not fully explain, for example, the apparent ‘resistance’ to digoxin in hyperthyroidism. The most important digoxin-drug interactions are those involving quinidine and drugs which deplete the body of potassium. Plasma (or serum) digoxin concentration measurement may be of value in the diagnosis of toxicity or undertreatment, in overdose and in changing treatment in patients with renal impairment or on long term therapy.
Prazosin is a selective α1-adrenoceptor antagonist which is useful alone or in combination for the treatment of hypertension and heart failure. Unlike many other antihypertensive drugs, the action of prazosin appears to be closely related to its concentration in plasma or whole blood. Prazosin is variably absorbed, is subject to first-pass metabolism, and is eliminated almost entirely as metabolites of much lower hypotensive activity than the parent drug. Prazosin is highly bound to plasma and tissue proteins. The influences of renal, hepatic and cardiac disease on the disposition of prazosin are reviewed, as are the effects of pregnancy and ageing. The optimum use of prazosin in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.
The number of studies on drug interactions with Cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, Ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active. Cimetidine does not alter plasma protein binding of other drugs, but reduces the volumes of distribution of labetolol, lignocaine (lidocaine), Imipramine and pethidine (meperidine) by unknown mechanisms. Cimetidine increases the plasma concentrations of drugs in a wide range of therapeutic classes. A number of physiological, pathological and drug-related factors alter the degree of inhibition of hepatic drug clearance by cimetidine. In certain patients with already depressed drug clearance (e.g. the elderly, the cirrhotic), cimetidine will further decrease drug clearance to a potentially dangerous extent. This reduction in drug clearance is greater following enzyme induction by rifampicin or phenytoin or in smokers, although findings in the latter group have been inconsistent. Cimetidine will not fully attenuate the induction of drug metabolism by the above agents. The degree of inhibition of drug metabolism by cimetidine is of the order of 10 to 20% with a daily dosage of 300 to 400mg, 20 to 30% with 400 to 800mg, 30 to 40% with 800 to 1600mg: with daily dosages greater than 2000mg, the inhibition is between 40 and 50%, depending upon the substrate used. The onset of inhibition is rapid: maximum inhibition occurs 24 hours after starting cimetidine, and is maintained for at least 30 days if cimetidine is continued. The recovery rate is also rapid and clearance rates return to baseline 2 to 3 days after stopping cimetidine, depending on the half-life of the interacting drug; in the case of warfarin, plasma concentrations will not return to the precimetidine level for at least 7 days. Because of the large number of drugs which can potentially interact with cimetidine, the physician should suspect a drug interaction when an abnormal response is encountered in any patient coprescribed cimetidine. Toxicity may occur for drugs with a narrow therapeutic index, e.g. theophylline, Phenytoin, warfarin and the majority of the antiarrhythmic, antidepressant and antipsychotic drugs for which clinical evidence of the drug interactions has been reported. These patients can be managed by: (a) reducing the dose of the interacting drug; (b) selecting a drug of similar therapeutic efficacy that does not interact with cimetidine; or (c) selecting other antiulcer drugs which do not interact. The need for cimetidine or other antiulcer therapy should also be assessed. Although cimetidine interacts with a large number of drugs, reports of incidents of drug toxicity are uncommon. This may be due to the fact that physicians are well aware of those drugs with a narrow therapeutic index which interact clinically with cimetidine and have taken appropriate action, or the fact that the majority of drugs have a wide therapeutic index, so that a 50% increase in plasma concentration would not be deleterious to the patient.
Sodium valproate (valproic acid) has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent. Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies. Valproic acid is available in different oral formulations such as solutions, tablets, enteric-coated capsules and slow-release preparations. For most of these formulations bioavailability approaches 100%, while the absorption half-life varies from less than 30 minutes to 3 or 4 hours depending on the type of preparation used. Once absorbed, valproic acid is largely bound to plasma proteins and has a relatively small volume of distribution (0.1 to 0.4 L/kg). Its concentration in CSF is approximately one-tenth that in plasma and is directly correlated with the concentration found in tears. At therapeutic doses, valproic acid half-life varies from 10 to 20 hours in adults, while it is significantly shorter (6 to 9 hours) in children. Valproic acid undergoes extensive liver metabolism. Numerous metabolites have been positively identified and there is reasonable evidence that several of them contribute to its pharmacological and toxic actions. In fact, several valproic acid metabolites have anti-convulsant properties, while many of the side effects it may cause (e.g. those related to hyperammonaemia or liver damage) are most often observed in patients previously treated with phenobarbitone. This could indicate that induction of liver enzymes is responsible for the formation of toxic valproic acid metabolites.
Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. Healthy men and nonpregnant women aged 18-45 years with a body mass index of </=30 kg/m(2) each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum observed drug plasma concentration (C(max)). Safety and tolerability were also assessed. A total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the C(max) or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the C(max) of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events. Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.
Although metabolite-to-parent drug concentration ratios in hair have been suggested as a possible tool to study the metabolism of drugs in a non-invasive way, no studies are available that evaluated this in a systematic way. Cytochrome P450 (CYP) 1A2 is a drug-metabolizing enzyme characterized by large inter-individual differences in its activity. The standard approach for CYP1A2 phenotyping is to determine the paraxanthine/caffeine ratio in plasma at a fixed timepoint after intake of a dose of the CYP1A2 substrate caffeine. The aim of this study was to evaluate whether paraxanthine/caffeine ratios measured in hair samples reflect the plasma-based CYP1A2 phenotype. Caffeine and paraxanthine concentrations were measured in proximal 3 cm segments of hair samples from 60 healthy volunteers and resulting paraxanthine/caffeine ratios were correlated with CYP1A2 phenotyping indices in plasma. Paraxanthine/caffeine ratios in hair ranged from 0.12 to 0.93 (median 0.41); corresponding ratios in plasma ranged from 0.09 to 0.95 (median 0.40). A statistically significant correlation was found between ratios in hair and plasma (r = 0.41, p = 0.0011). However, large deviations between ratios in both matrices were found in individual cases. Although the influence of several factors on paraxanthine/caffeine ratios and hair-plasma deviations was investigated, no evident factors explaining the observed variability could be identified. The variability between hair and plasma ratios complicates the interpretation of hair paraxanthine/caffeine ratios on an individual basis and, therefore, compromises their practical usefulness as alternative CYP1A2 phenotyping matrix.
Scatter plot of observed versus individual model-predicted caffeine plasma concentrations (n = 67) using the individual maximum a priori (MAP) Bayesian posterior parameter values of ka, VS1 and CLS1, based on the population median parameter values and their SDs as the MAP Bayesian priors, in the population (r = 0.98, p < 0.0001). CLS1 = fractional systemic caffeine clearance (slope of plasma clearance to bodyweight); ka = absorption rate constant; VS1 = fractional volume of distribution (slope of volume of distribution to bodyweight). 
Probit transformations of systemic caffeine clearance (CLS1) and elimination rate constant (kel) data. The ordinates of the figures are cumulative frequency distributions in probit units. (a) Probit plot of untransformed CLS1 values as estimated with the nonparametric expectation maximisation (NPEM) method (abscissa); (b) probit plot of untransformed kel values as estimated with the NPEM method (abscissa); (c) probit plot of logarithmically transformed (to the base 10) CLS1 values (abscissa); (d) probit plot of logarithmically transformed (to the base 10) kel values (abscissa). 
To explore the ability of the nonparametric expectation maximisation (NPEM) method of population pharmacokinetic modelling to deal with sparse data in estimating systemic caffeine clearance for monitoring and evaluation of cytochrome P450 (CYP) 1A2 activity. Nonblind, single-dose clinical investigation in 34 non-related adult Bulgarian Caucasians (18 women and 16 men, aged between 18 and 62 years) with normal and reduced renal function. Each participant received oral caffeine 3 mg/kg. Two blood samples per individual were taken according to the protocol for measuring caffeine plasma concentrations. A total of 67 measured concentrations were used to obtain NPEM estimates of caffeine clearance. Paraxanthine/caffeine plasma ratios were calculated and correlated with clearance estimates. Graphical methods and tests for normality were applied and parametric and nonparametric statistical tests were used for comparison. NPEM median estimates of caffeine absorption and elimination rate constants, k(a) = 4.54 h(-1) and k(el) = 0.139 h(-1), as well as of fractional volume of distribution and plasma clearance, V(S1) = 0.58 L/kg and CL(S1) = 0.057 L/h/kg, agreed well with reported values from more 'data rich' studies. Significant correlations were observed between paraxanthine/caffeine ratios at 3, 8 and 10 hours and clearance (Spearman rank correlation coefficients, r(s), >0.74, p </= 0.04). Sex or renal function caused no significant differences in clearance. Heavy smokers and drinkers showed 2-fold higher CYP1A2 activity. Normality tests and graphical methods of analysing caffeine clearance supported a non-Gaussian and multicomponent distribution of CYP1A2 activity. Collectively, the results show that the NPEM method is suitable and relevant for large-scale epidemiological studies of population phenotyping for cancer susceptibility and for abnormal liver function by monitoring CYP1A2 activity based on sparse caffeine data.
Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in paediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as paediatric to adult relative intrinsic clearance per mg of hepatic microsomal protein, based on the deconvolution of in vivo pharmacokinetic data and by accounting for the impact of known clinical condition on hepatic unbound intrinsic clearance for caffeine and theophylline as markers of CYP1A2 activity and for midazolam as a marker of CYP3A4 activity. The function for CYP1A2 describes an increase in relative intrinsic metabolic clearance from birth to 3 years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic clearance, reaching the adult value at about 1.3 years of age. The new models were validated by showing improved predictions of the systemic clearances of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared with those using a previous ontogeny function based on in vitro data (alfentanil: mean squared prediction error 3.0 vs. 6.8; ropivacaine: mean squared prediction error 2.3 vs.14.2). When implementing enzyme ontogeny functions, it is important to consider potential confounding factors (e.g. disease) that may affect the physiological conditions of the patient and, hence, the prediction of net in vivo clearance.
Objective: To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using in vitro and in vivo studies in humans. Methods: Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18-65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports. Results: The in vitro results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum plasma drug concentration (C(max)) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC(infinity) and C(max) increased by only 13% (90% CI 7, 18) and 7% (90% CI 2, 14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated. Conclusion: Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.
The pharmacokinetics of almotriptan are linear over a range of oral doses up to 200mg in healthy volunteers. The compound has a half-life of approximately 3 hours. Almotriptan is well absorbed after oral administration and the mean absolute bioavailability is 69.1%. Maximal plasma concentrations are achieved between 1.5 and 4 hours after dose administration; however, within 1 hour after administration, plasma concentrations are approximately 68% of the value at 3 hours after administration. Food does not significantly affect almotriptan absorption. Almotriptan is not highly protein bound and is extensively distributed in the body. Approximately 50% of an almotriptan dose is excreted unchanged in the urine; this is the predominant single mechanism of elimination. Renal clearance is mediated, in part, through active tubular secretion, while the balance of the almotriptan dose is metabolised to inactive compounds. The predominant route of metabolism is via monoamine oxidase-A, and cytochrome P450 (CYP) mediated oxidation (via CYP3A4 and CYP2D6) occurs to a minor extent. Almotriptan clearance is moderately reduced in elderly subjects, but the magnitude of this effect does not warrant a dose reduction. Sex has no significant effect on almotriptan pharmacokinetics. Almotriptan pharmacokinetic parameters do not differ between adolescents and adults, and absorption is not affected during a migraine attack. As expected, renal dysfunction results in reduced clearance of almotriptan. Patients with moderate-to-severe renal dysfunction should use the lowest dose of almotriptan and the total daily dose should not exceed 12.5 mg. Similar dosage recommendations are valid for patients with hepatic impairment, based on the clearance mechanisms for almotriptan. Drug-drug interaction studies were conducted between almotriptan and the following compounds: fluoxetine, moclobemide, propranolol, verapamil and ketoconazole. No significant pharmacokinetic or pharmacodynamic interactions with almotriptan were observed for fluoxetine or propranolol. Almotriptan clearance was reduced, to a modest degree, by moclobemide and verapamil, which was consistent with the contribution of monoamine oxidase-A and CYP3A4 to the metabolic clearance of almotriptan. Although ketoconazole has a greater effect on almotriptan clearance than verapamil, no dosage adjustment is required when almotriptan is given with these drugs.
Binding and kinetic model for canakinumab and interleukin-1b. CL D = clearance for drug; CL L = clearance for ligand; CL X = clearance for complex; IL = interleukin; k a = absorption rate; K D = binding dissociation constant between drug and ligand; PS D = intercompartmental permeability-surface area coefficient for drug ; PS L = intercompartmental permeability-surface area coefficient for ligand; RL I = production rate of ligand; V C = central volume; V P = peripheral volume. 
Canakinumab serum clearance (estimated by the pharmacokinetic-binding model) vs dose. CL= serum clearance; IV = intravenous; SC = subcutaneous.
Serum concentration-time profiles of canakinumab in adult cryopyrin-associated periodic syndrome patients, rhesus monkeys, marmoset monkeys (mean ± standard deviation) and mice after a single intravenous administration of canakinumab. The data are taken from study CACZ885A2102 (NCT00487708)[16] for the cryopyrin-associated periodic syndrome pharmacokinetic profile, and from animal pharmacokinetic studies (Novartis preclinical data) for marmosets (5 mg/kg intravenous), CD-1 mice (10 mg/kg intravenous) and rhesus monkeys (2 mg/kg intravenous). CAPS= cryopyrin-associated periodic syndromes; IV = intravenous.
Canakinumab is a high-affinity human monoclonal anti-interleukin-1β (IL-1β) antibody of the IgG1/κ isotype designed to bind and neutralize the activity of human IL-1β, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1β. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis. Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70 kg, slow serum clearance (0.174 L/day) was observed with a low total volume of distribution at steady state (6.0 L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight. During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.
The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dosenormalised area under the concentration-time curve from zero to infinity (AUC0-∞) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(−) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(−) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC-∞ of each enantiomer increased proportionately with dose. The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dosenormalised Cmax and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(−) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearances of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.
Screening of articles identified using the search strategy in PubMed. CL = clearance; PBPK study = physiologically based pharmacokinetic study; PK = pharmacokinetic; V d = volume of distribution.
Therapeutic classes of drugs studied in 458 population pharmacokinetic articles published from 2000 to 2007. CV = cardiovascular.
The percent success of inclusion of physiological covariates considered on drug clearance. Error bars are the 95% confidence interval calculated using the normal approximation to the binomial distribution. CL CR = creatinine clearance; n = number of models; S CR = serum creatinine.
Exponents estimated on total body weight to describe drug clearance in 56 studies. The dashed line indicates median = 0.65; the solid line indicates density function. TBW = total body weight.
The percent success of identifying a nonlinear relationship between total body weightand drug clearance from 199 models that (i) identified any relationship between body size and drug clearance and (ii) reported the range of subject weight for the study population. Error bars are the 95% confidence interval using the normal approximation to the binomial distribution. TBW = total body weight; * significant difference between counts for groups (p < 0.01) determined by one-tailed Z test with Yates continuity correction applied to the chi-squared (w 2 ) distribution.  
Background: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. Aim: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. Methods: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a 'nonlinear' relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting 'other' relationships (e.g. linear increase in CL with TBW, ideal body weight or height). Results: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)(2/3), or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. Conclusions: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.
Trans-resveratrol is a polyphenol, which is found in red wine and has cancer chemo-preventive properties and disease-preventive properties. The pharmacokinetics of trans-resveratrol have been investigated in single-dose studies and in studies with relatively low dosages. The present study aimed to investigate the steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol). This was a two-period, open-label, single-arm, within-subject control study in eight healthy subjects. The steady-state 12-hour pharmacokinetics of trans-resveratrol 2000 mg twice daily were studied with a standard breakfast, a high-fat breakfast, quercetin 500 mg twice daily and 5% alcohol 100 mL. Trans-resveratrol plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The mean (SD) area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and maximum plasma concentration (C(max)) of trans-resveratrol were 3558 (2195) ng * h/mL and 1274 (790) ng/mL, respectively, after the standard breakfast. The high-fat breakfast significantly decreased the AUC(12) and C(max) by 45% and 46%, respectively, when compared with the standard breakfast. Quercetin 500 mg twice daily or 5% alcohol 100 mL did not influence trans-resveratrol pharmacokinetics. Diarrhoea was reported in six of the eight subjects. Significant but not clinically relevant changes from baseline were observed in serum potassium and total bilirubin levels. Trans-resveratrol 2000 mg twice daily resulted in adequate exposure and was well tolerated by healthy subjects, although diarrhoea was frequently observed. In order to maximize trans-resveratrol exposure, it should be taken with a standard breakfast and not with a high-fat meal. Furthermore, combined intake with quercetin or alcohol did not influence trans-resveratrol exposure.
Oseltamivir is the ester-type prodrug of the neuraminidase inhibitor oseltamivir carboxylate. It has been shown to be an effective treatment for both seasonal influenza and the recent pandemic 2009 A/H1N1 influenza, reducing both the duration and severity of the illness. It is also effective when used preventively. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of possible therapeutic drug monitoring. According to the currently available literature, the pharmacokinetics of oseltamivir carboxylate after oral administration of oseltamivir are characterized by mean ± SD bioavailability of 79 ± 12%, apparent clearance of 25.3±7.0L/h, an elimination half-life of 7.4±2.5 hours and an apparent terminal volume of distribution of 267 ± 122 L. A maximum plasma concentration of 342±83 μg/L, a time to reach the maximum plasma concentration of 4.2 ± 1.1 hours, a trough plasma concentration of 168±32mg/L and an area under the plasma concentration-time curve from 0 to 24 hours of 6110 ± 1330 mg · h/L for a 75 mg twice-daily regimen were derived from literature data. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Interpatient variability is moderate (28% in apparent clearance and 46% in the apparent central volume of distribution); there is no indication of significant erratic or limited absorption in given patient subgroups. The in vitro pharmacodynamics of oseltamivir carboxylate reveal wide variation in the concentration producing 50% inhibition of influenza A and B strains (range 0.17–44 μg/L). A formal correlation between systemic exposure to oseltamivir carboxylate and clinical antiviral activity or tolerance in influenza patients has not yet been demonstrated; thus no formal therapeutic or toxic range can be proposed. The pharmacokinetic parameters of oseltamivir carboxylate after oseltamivir administration (bioavailability, apparent clearance and the volume of distribution) are fairly predictable in healthy subjects, with little interpatient variability outside the effect of renal function in all patients and bodyweight in children. Thus oseltamivir carboxylate exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics. However, there is a lack of clinical study data on naturally infected patients. In addition, the therapeutic margin of oseltamivir carboxylate is poorly defined. The usefulness of systematic therapeutic drug monitoring in patients therefore appears to be questionable; however, studies are still needed to extend the knowledge to particular subgroups of patients or dosage regimens.
The importance of predicting human pharmacokinetics during compound selection has been recognized in the pharmaceutical industry. To this end there are many different approaches that are applied. In this study we compared the accuracy of physiologically based pharmacokinetic (PBPK) methodologies implemented in GastroPlus™ with the one-compartment approach routinely used at Pfizer for human pharmacokinetic plasma concentration-time profile prediction. Twenty-one Pfizer compounds were selected based on the availability of relevant preclinical and clinical data. Intravenous and oral human simulations were performed for each compound. To understand any mispredictions, simulations were also performed using the observed clearance (CL) value as input into the model. The simulation results using PBPK were shown to be superior to those obtained via traditional one-compartment analyses. In many cases, this difference was statistically significant. Specifically, the results showed that the PBPK approach was able to accurately predict passive distribution and absorption processes. Some issues and limitations remain with respect to the prediction of CL and active transport processes and these need to be improved to further increase the utility of PBPK modelling. A particular advantage of the PBPK approach is its ability to accurately predict the multiphasic shape of the pharmacokinetic profiles for many of the compounds tested. The results from this evaluation demonstrate the utility of PBPK methodology for the prediction of human pharmacokinetics. This methodology can be applied at different stages to enhance the understanding of the compounds in a particular chemical series, guide experiments, aid candidate selection and inform clinical trial design.
Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patient-focused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process. The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM. Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value. In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: 'Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?' We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit. Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to 'treat the patient and not the level'. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.
Top-cited authors
Mary Ensom
  • University of British Columbia - Vancouver
Thomas Eissing
Teun van Gelder
  • Leiden University Medical Centre
Dennis A Hesselink
Julie Derving Karsbøl