Recently, a new latanoprost ophthalmic solution containing cyclodextrins was developed. The purpose of the present work was to compare the stability, clinical efficacy, and adverse effect profile of this formulation with the innovator product. The innovator formulation was stable at 4 degrees C but exhibited degradation at higher temperatures, whereas the cyclodextrin-containing formulation was stable at temperatures up to 40 degrees C. Formulations were assayed in a randomized double-blind clinical study in patients with primary open-angle glaucoma and/or ocular hypertension. Both latanoprost ophthalmic solutions produced comparable reduction of intraocular pressure. Conjunctival hyperemia was observed in 11.9% and 11.3% of the patients treated with the innovator and the cyclodextrin-containing formulations, respectively. There were no significant differences between the 2 ophthalmic solutions in efficacy or in the measured adverse effect. It is concluded that these 2 latanoprost ophthalmic solutions yield comparable efficacy and adverse effect outcomes. The cyclodextrin-containing formulation, however, has an improved stability.
Oesclim (Laboratoires Fournier, Dijon, France), also known as Esclim or Esclima, is a new estradiol transdermal delivery system (TDS) developed for the treatment of menopausal vasomotor symptoms. This open, randomized, three-way crossover study compared in 24 healthy postmenopausal women the pharmacokinetics of estradiol after a single 4-day application of Oesclim 50, Oesclim 100, and Vivelle 0.05 (CibaGeneva Pharmaceuticals, Summit, NJ; known as Menorest 50 in Europe, Rhône-Poulenc Rorer) on the upper buttock. Serum estradiol concentrations were determined by a validated radioimmunoassay method from samples taken before and during each TDS application. The concentration-time profiles for Vivelle 0.05 and Oesclim 50 were comparable with a similar absorption rate, giving a maximum concentration (Cmax) of 49 and 53 pg/mL above baseline, respectively, followed by a plateau throughout the 96-hour application period. At the end of this period, mean corrected estradiol concentrations were 18 and 19 pg/mL, respectively. The estradiol serum concentrations obtained after an application of Oesclim 100 were approximately twice as high than with Oesclim 50. All products were well tolerated, but skin intolerance was more frequent with Vivelle 0.05 (4 patients; four reports) and Oesclim 100 (3 patients; three reports) than with Oesclim 50 (none). Problems of imperfect adhesion were more than five times as frequent with Vivelle 0.05 (44%) than with Oesclim (8%).
To investigate the circadian and blood pressure (BP) reduction obtained with timolol maleate 0.5% solution administered twice daily versus timolol 0.1% in gel-forming carbomer administered in the morning in patients with primary open-angle glaucoma (POAG).
This investigator-masked, crossover study prospectively enrolled naive POAG patients not receiving systemic cardiovascular medications. Following a baseline evaluation, they were randomized to receive a timolol 0.5% solution or timolol 0.1% hydrogel for 2 months and then switched to the alternative medication for a further 2 months. Intraocular pressure (IOP) phasing (sitting Goldmann tonometry at 10 am, 2 pm, 6 pm, and 10 pm and supine Perkins tonometry at 2 am and 6 am) and ambulatory home BP monitoring were measured at baseline and after each treatment period.
On the basis of a prospective sample size estimate, 28 patients were analyzed. Mean 24-hour IOP decreased from 23.1 ± 0.7 mm Hg at baseline to 18.9 ± 0.6 mm Hg after timolol 0.5% and 18.9 ± 0.8 mm Hg after timolol 0.1% hydrogel (P < .001); both formulations also significantly decreased diurnal, nocturnal, and individual time point IOP in a statistically similar manner. Systolic and diastolic BP remained generally unaffected. The calculated diastolic ocular perfusion pressure was either unaffected or tended to increase with either medication.
Both timolol formulations show similar and significant circadian efficacy and have minimal effects on BP and calculated diastolic ocular perfusion pressure.
This study investigated possible effects of brimonidine tartrate 0.2% and apraclonidine 0.5% on pupil diameter. Ten subjects between 20 and 40 years of age participated. A Colvard pupillometer (Oasis Medical) was used to measure pupil diameter. Baseline and serial measurements were obtained at 3 luminance levels (>6.4, <0.82-0.4, and <0.2-0.02 cd/m(2)) during a 4-hour interval following instillation of 1 drop of brimonidine tartrate 0.2% or apraclonidine 0.5% in one eye versus a placebo in the contralateral eye. The measurements for each drug were obtained on different days. A nested random effects model controlling for subject's age, race, and sex was used for statistical analysis. A maximum reduction in pupil diameter was observed at 90 minutes from instillation (1.40 mm at >6.4 cd/m(2), 1.69 mm at <0.82-0.4 cd/m(2), and 1.55 mm at <0.2-0.02 cd/m(2)) for brimonidine tartrate 0.2%. At all time intervals and illumination levels, miosis (P < .01) occurred. Apraclonidine 0.5% did not produce a significant effect on pupil diameter. Brimonidine tartrate 0.2% produced a moderate miotic effect. No effect was observed for apraclonidine 0.5%. A predominant agonistic effect on α-2 receptors of the iris dilator may explain this behavior.
The pharmacokinetics, safety, and tolerability of doripenem in healthy subjects were evaluated in 2 studies. Study 1 was a double-blind, randomized, placebo-controlled dose-escalation study in which doripenem was administered for 7 days by infusion over 30 minutes (500 mg) or 1 hour (1000 mg). Study 2 was an open-label, randomized, 3-way crossover study in which each subject received a single dose of each of the following doripenem treatments on separate occasions: 500 mg infused over 1 hour, 500 mg infused over 4 hours, and 1000 mg infused over 4 hours. Doripenem exhibited linear pharmacokinetics with concordance between the studies for pharmacokinetic parameters. Doripenem did not accumulate with repeated dosing over 7 days. The area under the plasma concentration-time curve (AUC) for doripenem 500 mg infused over 1 hour versus 4 hours was bioequivalent, and the AUC and Cmax increased proportionally with dose for the 500- and 1000-mg doses administered over 4 hours. These results, along with the stability profile of doripenem, support its use as a prolonged infusion. All regimens of doripenem were safe and well tolerated.
PRX-00023 is a novel, nonazapirone 5-HT1A agonist in clinical development for treatment of affective disorders. The objectives of the initial clinical phase I studies (a single ascending dose study and multiple dose-ascending and high-dose titration studies) were to measure the pharmacokinetics, pharmacodynamic (neuroendocrine) effects, and tolerability of PRX-00023 in healthy subjects. The studies evaluated 10-mg to 150-mg doses of PRX-00023 in up to 112 healthy male and female subjects aged 18 to 54 years. Single and multiple oral doses of PRX-00023 were found to be safe and well tolerated in healthy subjects. PRX-00023 was absorbed relatively rapidly, with a tmax of 0.5 to 2 hours, and eliminated with a half-life of approximately 12 hours. PRX-00023 treatment transiently increased blood prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 5-HT1A agonist.
UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human gamma-globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10(8)(mol/L)(-1), indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.
The prediction of a human clearance (CL) value for UCN-01, an extreme example of vertical allometry (a large overprediction by allometric scaling), was examined using commonly used simple allometry and the "rule of exponents," as well as a newly proposed model, which quantitatively incorporates plasma protein-binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN-01 by about 5000- and 1750-fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20-fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN-01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics.
HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate), an oral anticholinesterase, enhances memory in rodents and may be useful in treating Alzheimer's disease (AD). To assess adverse events in relation to dosage and plasma drug levels, 24 hospitalized AD subjects were randomly assigned to receive placebo or HP 029 for 10 days in a double-blind, sequential escalation study. Maximum daily dosages were 450 mg (group 1), 300 mg (group 2), and 225 mg (group 3), divided into three doses per day. The group 1 trial was discontinued on day 5 because one subject, 6 hours following the second of three scheduled 150-mg doses, had a tonic seizure after protracted vomiting and hyperventilation; adverse events in other patients included nausea, vomiting, abdominal cramps, diarrhea, dizziness, and syncope. Adverse events were generally less severe in group 2, but only two of six HP 029 subjects could complete the trial at 300 mg/day. All group 3 subjects completed the trial at 225 mg/day with drug related, mild adverse events (nausea, vomiting, lacrimation, rhinorrhea) in only two subjects. Although mean plasma drug levels were related to adverse events across dosage groups, they did not adequately predict the occurrence or severity of adverse events in individual subjects. The 225 mg/day dose appears to be safe for use in multicenter outpatient trials of HP 029 efficacy in AD. Further patient studies are ongoing to determine the relation of specific subject characteristics to the metabolic profile of HP 029 and biological response.
Velnacrine (HP 029; 1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is an investigational drug being studied in patients with Alzheimer's disease. In this open, randomized, crossover study, 24 healthy, elderly men were given 100 mg of velnacrine on two different study days to assess the influence of food on the bioavailability of velnacrine. On the first day, subjects received drug either after an overnight fast or 15 minutes after completing a standard breakfast. Seven days later, the treatments were crossed over. Blood and urine samples were collected at specific times and various intervals, respectively, from all subjects before and after drug administration for up to 24 hours. Plasma and urine concentrations of velnacrine were determined by an HPLC method. Administration of velnacrine with food resulted in slightly lower peak plasma levels of unconjugated velnacrine, (175 vs 213 ng/ml) and delayed times-to-peak plasma levels, (2.5 vs 1.5 h) without affecting the AUCs and the t 1/2 of the drug. The amount of unconjugated velnacrine excreted in urine was slightly higher when the drug was taken with food (19 vs 17 mg), but renal clearance was not altered. These results indicate that food delayed the rate but not the extent of velnacrine absorption. The minor differences in Cmax and tmax may not be clinically meaningful. Therefore, velnacrine can be administered with or without food.
The pharmacokinetics, safety, and tolerance of 1,2,3,4-tetrahydro-9-aminoacridin-1-olmaleate (HP 029) a potential therapeutic agent for Alzheimer's disease, were assessed after multiple oral doses in a randomized double-blind, placebo controlled, ascending dose study in 56 healthy elderly men (14 per dose group). The subjects in the first three groups received 25, 50, or 100 mg two times a day and a fourth group was administered 100 mg velnacrine tid for 28 days. All subjects received a final dose on day 29. Subjects were confined for continuous observation during the 36-day study period. Blood and urine samples were collected for the pharmacokinetic assessment. There were no clinically important changes in the safety variables in both age groups after any dose. There was no evidence of hepatotoxicity when elderly men were given 100 mg tid for 28 days. Nine subjects reported one or two episodes of gastrointestinal (diarrhea) side effects (6 in the 100 mg bid group and 3 in the 100 mg tid dose group) during a 29-day trial. None required treatment or were discontinued from study. These results indicate that the safety and tolerance up to 100 mg tid for 28 days in healthy elderly men are acceptable. Velnacrine was rapidly absorbed after oral administration. There were dose-related increases in Cmax, AUCs, and amount of drug excreted in urine. During multiple dosing, the Cmax increased as a function of dose. The tmax and t1/2 were not affected by dosage nor multiple dosing. Steady state levels of velnacrine were reached between days 2 and 3 with no evidence of further accumulation of velnacrine thereafter. Approximately 11-30% of the administered dose was excreted in the urine over the course of the study. The favorable pharmacokinetic characteristics and acceptable safety and tolerance of multiple dosing oral doses of velnacrine support further testing of this compound for efficacy and safety in Alzheimer's patients.
1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)
Sitagliptin (MK-0431), an orally active, potent and selective DPP-IV inhibitor being developed for Type 2 diabetes mellitus, is a substrate for p-glycoprotein (Pgp). High dose cyclosporine A (CSA) was used as a probe Pgp inhibitor to evaluate the effect of potent Pgp inhibition on sitagliptin PK.METHODS8 healthy young men received Treatments A (single oral 600 mg dose of CSA[NEORAL™] with a single 100 mg oral sitagliptin dose) and B (single oral 100 mg sitagliptin dose alone) in an open-label, randomized, 2-period, crossover study, separated by a 2-week washout. Pre-specified bounds of[0.50, 2.00] were used for AUC GMR whether any alterations in MK-0431 PK was clinically meaningful.RESULTSSitagliptin with or without CSA was generally well tolerated. Sitagliptin AUC0-∞ GMR (1.29) with 90% CI[1.24, 1.34], and Cmax GMR (1.68) with 90% CI[1.35, 2.08] indicated modest effects by CSA and unlikely to be clinically relevant. There were no meaningful differences in CLr, apparent t1/2 or C24hr.CONCLUSIONS
This study with high dose CSA confirmed that sitagliptin was a substrate for Pgp. Co-administration of CSA with sitagliptin only modestly increased Cmax of sitagliptin without a meaningful effect on overall exposure. Given only modest alterations in PK (i.e., on Cmax) with a highly potent Pgp inhibitor, the magnitude of changes in sitagliptin PK with other medications that are Pgp inhibitors, albeit less potent ones, is unlikely to be clinically meaningful.Clinical Pharmacology & Therapeutics (2005) 79, P63-P63; doi: 10.1016/j.clpt.2005.12.225
NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated.
NXY-059 is a novel free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. Any effect of NXY-059 on hemostasis may be important when treating stroke patients. This phase I randomized, double-blind, placebo-controlled, 3-period crossover study compared the effect of NXY-059, desmopressin, and placebo on bleeding time, platelet aggregation, and adhesion in 30 healthy volunteers. NXY-059 did not prolong bleeding time compared with placebo: mean (SD) time for NXY-059, 369.5 seconds (125.0 seconds) versus placebo, 369.1 seconds (136.0 seconds). There were no significant effects on platelet aggregation or adhesion. At a mean unbound plasma concentration (Cu(ss)) of 335 micromol/L, NXY-059 was well tolerated, with no major safety concerns identified. In conclusion, NXY-059 does not appear to affect primary hemostasis.
The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.
ARD-07 (also known as EP01572) is a peptidomimetic growth hormone secretagogue that can be administered orally. The primary objective of this study is to determine the effects of a meal on the oral bioavailability of ARD-07 after a single oral dose (0.5 mg/kg). In addition, the pharmacodynamic effects (growth hormone release, insulin-like growth factor-1 concentrations) and the tolerability of ARD-07 are investigated in this open-label, randomized, crossover study. Sixteen healthy subjects (8 males, 8 females) receive ARD-07 on 2 different days; the treatment consists of a single oral dose of ARD-07 (0.5 mg/kg body weight), once with and the second day without a test meal. Plasma kinetics of ARD-07 and pharmacodynamic effects are quantified by specific assays. Results are given as mean +/- SEM: The area under the curve for 0 to 24 hours is approximately twice as high without food (27.8 +/- 4.1) than with food (13.7 +/- 1.2; P = .002). The maximum observed ARD-07 concentration relative to dose administration (C(max)) is more than twice as high without food (10.6 +/- 1.6 ng/mL) than with food (4.4 +/- 0.5 ng/mL; P = .001). C(max) of growth hormone occurs at a significantly (P = .001) later stage with food (C(max) = 13.0 +/- 3.5 ng/mL) than without food (37.1 +/- 5.3 ng/mL). Food has a marked effect on the absorption of ARD-07: there is a significant difference in bioavailability between administration of oral ARD-07 with and without food.
MK-0767, a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, has been studied as a potential treatment of type 2 diabetes and dyslipidemia. The pharmacokinetics and interconversion of (+)-(R)-MK-0767 and (-)-(S)-MK-0767 were evaluated following oral administration of each single enantiomer and the racemate to healthy subjects. The results demonstrate that, consistent with in vitro experiments, chiral inversion occurs rapidly in vivo, and interconversion equilibrium favors (+)-(R). After all treatments, a stable ratio (R/S) of 2 to 2.5 was achieved within 8 hours in most individuals, congruent with model-based estimates of interconversion half-life. In addition, the pharmacokinetics of each enantiomer were generally similar regardless of treatment. Modeling and simulation of enantiomer disposition suggest that the observed predominance of (+)-(R)-MK-0767 in plasma may result from differential volumes of distribution between (-)-(S) and (+)-(R), preferential conversion from (-)-(S) to (+)-(R), or a combination of these, but not faster clearance of (-)-(S) compared to (+)-(R).
The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.
This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.
HBY-097 (HBY), an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI), and indinavir (IDV) share a common metabolic pathway, cytochrome P4503A4 (CYP3A4), and may clinically be used together as well as with zidovudine (ZDV). Thus, the potential pharmacokinetic (PK) interaction between these drugs was evaluated. HBY (500 mg Q8H), IDV (800 mg Q8H), and ZDV (200 mg Q8H) were given to 8 HIV-infected subjects. Serial plasma samples were collected at baseline (ZDV and IDV alone) and day 11 (all 3 drugs) to determine PK parameters using noncompartmental analysis. PK parameters for ZDV in the presence and absence of HBY were not appreciably different. However, both the maximum (Cmax) and minimum (Cmin) concentrations of IDV were significantly reduced, from a mean of 7514 +/- 1636 and 146 +/- 81 mcg/L to 4725 +/- 2494 mcg/L and 54 +/- 24 mcg/L (p < .05) after addition of HBY. Furthermore, apparent clearance (CL/F) of IDV before and after 11 days of concomitant HBY administration was significantly higher, from 0.69 +/- 0.14 to 1.94 +/- 0.63 L/h/kg (p < .05) with an associated reduction in area under the curve (AUC0-8) from 16,034 +/- 4903 to 6134 +/- 2701 mg/L/h (p < .05). The increase in IDV CL/F is consistent with the observed metabolic induction effects of other NNRTIs. The results of this trial showed that HBY significantly alters the pharmacokinetic parameters of IDV at the dose studied.
A phase I dose-response study of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol HCl (MK-447) was performed with the following oral doses: 6.25, 12.5, 25, 50, and 100 mg. Each volunteer served as his own control. The study was carried out in double-blind fashion on a 5-Gm Na and K diet with a minimum 2000 ml fluid intake. Urine was fractionated and analyzed for sodium, chloride, potassium, calcium, uric acid, and volume. Comparisons (MK-447 minus control values) of the 24-hour total sodium, calcium, potassium, and volume excretion rates at 6.25, 25 and 100 mg MK-447 were as follows: sodium, 195, 345, and 528 muEq/min; chloride, 191, 365, and 756 muEq/min; potassium, 77, -3, and 65 muEq/min; and volumes, 1, 3.4 and 11.7 ml/min. MK-447 did not alter calcium excretion. Uric acid excretion was observed to decrease as the dose of MK-447 was increased, however, the serum uric acid level always remained within normal limits. MK-447 did not alter the physiologic parameters but did produce symptoms of volume contraction at 100 mg. Because no further dose increase was attempted, a plateau in the dose-response curve was not reached. Comparison of 100 mg MK-447 with 80 mg oral furosemide revealed similar potency and a somewhat longer duration of action for MK-447.
Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 microg/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.
Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects.
M100240 is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor-in phase II development. The pharmacokinetics of M100240 and MDL 100,173 were compared in young and elderly subjects. Pharmacokinetic data were obtained from 12 young (ages 18-45 years, 10 male, 2 female) and 12 elderly (ages 65-85 years, 7 male, 5 female) healthy subjects in a parallel-group, open-label study. Following an overnight fast, subjects received a single 25-mg oral dose of M100240. Serial plasma concentrations of M100240 and MDL 100,173 were determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, and pharmacokinetic parameters were calculated with noncompartmental methods. Single-dose treatment with M100240 was well tolerated in both groups of subjects, with no clinically significant changes in vital signs, ECG recordings, or laboratory safety parameters. M100240 was rapidly absorbed and converted to MDL 100,173, with M100240 concentrations no longer detectable at 3 to 4 hours postdose in both groups. The pharmacokinetics of the pharmacologically active MDL 100,173 were similar for both groups. Although maximum concentrations of M100240 were generally higher in elderly versus young subjects (C(max) 0.48 ng/mL vs. 0.17 ng/mL), systemic availability of M100240 was quite low and variable with plasma, and this apparent difference in parent drug exposure is unlikely to have important clinical implications. No age-related differences in the pharmacokinetic parameters of MDL 100,173 (C(max) 8.16 vs. 9.62 ng/mL, t(max) 1.25 vs. 1.5 h, AUC((0-last)) 81.6 vs. 72.2 ng x h/mL) were observed between young and elderly subjects, respectively. In conclusion, there are no age-related differences in the pharmacokinetics of MDL 100,173 between young and elderly subjects.
Ibuprofen is a peripherally acting nonsteroidal anti-inflammatory drug indicated fo ranalgesia, antipyresis, and various arthritic conditions. A solubilized 200 mg liquigel formulation of ibuprofen has been shown to have a more rapid rate of absorption compared with ibuprofen 200 mg tablets. Ibuprofen liquigels have a kinetic profile similar to ibuprofen suspension, with both a higher Cmax and an earlier tmax than any solid tablet. The objective of this single-dose, double-blind, triple-dummy, parallel-group study was to assess the time to onset of relief and overall analgesic efficacy of liquigel ibuprofen 400 mg, ketoprofen 25 mg compared with acetaminophen 1000 mg, and placebo in 239 patients with moderate or severe pain following third molar extractions. Treatments were compared over 6 hours using standard scales for pain intensity and relief and stopwatch onset of meaningful relief. All active treatments provided meaningful relief significantly faster compared with placebo. Ibuprofen provided significantly faster relief compared with acetaminophen and ketoprofen. By the end of the study (6 h), onset of meaningful relief was achieved by 36%, 99%, 96%, and 88% of the patients in the placebo, ketoprofen, ibuprofen, and acetaminophen groups, respectively. The median times to onset of relief were > 6 hours for placebo, 25.5 minutes for ketoprofen, 24.2 minutes for ibuprofen, and 29.9 minutes for acetaminophen. In addition, both ibuprofen and ketoprofen showed statistical superiority over acetaminophen at earlier time points on the time-effect curves for pain relief and pain intensity difference. Consistent results were seen with respect to the 6-hour summary efficacy variables: the three active treatments were significantly better than placebo, and ibuprofen was significantly better than both acetaminophen and ketoprofen. Liquigel ibuprofen 400 mg was shown to provide faster relief and superior overall efficacy compared with ketoprofen 25 mg, acetaminophen 1000 mg, and placebo. No serious adverse effects were reported in this single-dose study.
This randomized, double-blind, placebo-controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg--an effervescent solution and tablet--in 242 patients with moderate or severe pain following dental surgery. Onset of analgesia was determined using a two-stopwatch procedure. Analgesia was assessed over a 4-hour period. Treatments were compared using standard indexes of pain intensity and pain relief and summary measures. Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessments. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45 minutes). During the first 45 minutes after administration, effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen. The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen (45 minutes) compared to tablet acetaminophen (60 minutes). At 4 hours after administration, the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen. No other significant differences were observed between the active treatments. In conclusion, effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen.
A controlled, randomized, double-blind crossover study, in which the patients acted as their own controls, was carried out to test the efficacy of naproxen 500 mg x 2 versus acetaminophen 1000 mg x 4 for 3 days on the postoperative course following third molar surgery. Acetaminophen reduced the mean swelling on the 3rd postoperative day by 22.4% (p = 0.023) compared to that after naproxen. On the 6th postoperative day, there was 20.9% less mean swelling with naproxen (p = 0.44), although the total swelling measurements were much less than those measured on the 3rd postoperative day. Summed pain intensity (SUMPI3.5-11) on the day of surgery revealed no statistically significant difference between the acetaminophen or naproxen regimen with the exception of 0.5 hours (p = 0.002) and 1 hour (p = 0.009) after first medication when acetaminophen gave less pain than naproxen. Since the drug regimens were different, summed PI for the first acetaminophen dose interval (SUMPI3.5-6) and the first naproxen dose interval (SUMPI3.5-9) was calculated. There was a tendency toward a statistically significant difference in favor of acetaminophen for SUMPI3.5-6 (p = 0.055) but no statistically significant difference (p = 0.41) between the treatments with respect to SUMPI3.5-9. Naproxen was statistically superior (p < or = 0.002) to acetaminophen at 08:00, 12:00, and 16:00 hours on the 1st postoperative day and at 08:00 hours on the 2nd postoperative day, when the pain intensity level was lower than that on the day of surgery. A 3-day acetaminophen regimen reduces acute postoperative swelling better than naproxen on the 3rd postoperative day after third molar surgery but not on the 6th postoperative day when the total swelling is less.
A randomized, double-blind, within-patient, crossover study was carried out after bilateral "identical" surgical procedures using local anesthesia only. A 3-day tablet regime of racemic ketoprofen 75 mg or acetaminophen 1000 mg qid (x 4) was given starting 3 hours after surgery. Ketoprofen reduced objectively measured swelling 27.8% (p < 0.04) better than acetaminophen 3 days after surgery and 70.8% (p < 0.02) better than acetaminophen 6 days after surgery. The pain intensity (PI) was lower after ketoprofen than after acetaminophen from 2 to 6 hours after the first drug intake (all p-values < or = 0.03). Sum PI during the first (SUMPI3.5-6, p = 0.003) and second dose intervals (SUMPI6.5-9, p = 0.007) was lower for ketoprofen than for acetaminophen but not different for the third dose interval (SUMPI9.5-11, p = 0.53). Ketoprofen was a more effective analgesic than acetaminophen on the day of surgery (SUMPI3.5-11, p = 0.005). There was no difference (p > 0.05) between the treatments with respect to mouth opening, drug preference, global evaluation, or adverse reports. Adverse reports included stomach pain and diarrhea in both treatment groups. Ketoprofen 75 mg x 4 for 3 days reduces subjectively assessed pain and objectively measured swelling (i.e., anti-inflammatory effect) following third-molar surgery.
An open, randomized, three-period crossover study was conducted to compare the steady-state pharmacokinetics, pharmacodynamics, and tolerability of concomitant administration of BAY x 1005 and theophylline in 12 healthy volunteers. BAY x 1005 (250 mg twice daily; treatment A) and theophylline (400 mg twice daily; treatment B), were administered alone and concomitantly (treatment C) for 6 days with a final morning dose on day 7. The treatments were separated by washout periods of at least 5 days. Pharmacokinetic parameters were derived from concentrations of BAY x 1005 and theophylline as measured by high-performance liquid chromatography in plasma collected before the morning dose on days 5 and 6 and at various times on day 7 of each period until 24 hours after drug administration. Adverse events, vital signs, electrocardiograms, and clinical laboratory studies were monitored as safety parameters. Levels of leukotriene B4 (LTB4) were assessed in plasma collected on days 1 and 7. The treatments were well tolerated by all participants. The ratios of maximum concentration (Cmax) and area under the concentration-time curve for one 12-hour dosing interval (AUC tau) for treatment C versus B for theophylline on day 7 was 98% for both parameters. For BAY x 1005, the ratios of treatment C versus treatment A were 94% for Cmax and 101% for AUC tau. Plasma LTB4 remained virtually unchanged during either treatment. Steady-state concentrations of theophylline were not affected by concomitant BAY x 1005 intake, and addition of theophylline had no clinically relevant effect on steady-state plasma concentrations of BAY x 1005. The combination of theophylline and BAY x 1005 did not lead to a change in nature, intensity, or frequency of adverse events.
The authors evaluate the human safety, tolerability, pharmacokinetics, and pharmacodynamics of TZP-101, an agonist of the hGHS-R1a (ghrelin) receptor. Healthy subjects were randomized to either single-dose TZP-101 (20-600 microg/kg) or placebo by 30-minute intravenous infusion. Subjects underwent continuous cardiac monitoring, 12-lead electrocardiograms, and assessment for orthostatic hypotension, injection site tolerability, vital signs, and adverse events during the 24-hour postdose period. Blood and urine samples were collected for pharmacokinetic/pharmacodynamic assessment for 24 hours. Forty-eight subjects randomly received 1 of 6 TZP-101 doses or placebo. TZP-101 was well tolerated, with single episodes each of headache, lower abdominal pain, diarrhea, and dizziness. At the highest dose, 2 subjects experienced bradycardia. All events were self-limited. Mean arterial blood pressure and heart rate decreased from baseline approximately 45 to 60 minutes after infusion start at higher doses. No other significant changes were observed. Pharmacokinetic analysis revealed less than dose-proportional behavior of drug with low clearance (approximately 7 mL/h/kg), small volume of distribution (approximately 114 mL/kg), and half-life values of approximately 13 hours, which were independent of dose. Pharmacodynamic analyses suggested TZP-101, at doses as low as 40 microg/kg, expressed activity at the receptor. TZP-101 displayed a promising pharmacokinetic, pharmacodynamic, and safety profile for use in gastrointestinal motility disorders.
The influence of chlorthalidone (100 mg PO) on the pharmacokinetics and pharmacodynamics of Org 10172 (IV bolus injection of 3250 anti-Xa units), a low molecular weight heparinoid, was studied in six healthy male volunteers using an open randomized two-way crossover design. Chlorthalidone produced a slight decrease in clearance of anti-Xa activity from 7.1 +/- 1.0 to 6.6 +/- 0.8 mL/min and a decrease of the volume of distribution from 0.20 +/- 0.05 to 0.16 +/- 0.04 L/kg, whereas the volume of distribution of antithrombin activity increased from 0.14 +/- 0.05 to 0.26 +/- 0.10 L/kg (all differences P less than .05). During the entire study period no adverse events occurred. In summary, chlorthalidone showed separate effects on different fractions of Org 10172. The clinical implication of the slight change observed in plasma anti-Xa activity is likely to be limited, whereas the 80% increase in distribution volume of plasma antithrombin activity can not be defined as yet in terms of clinical relevance.
ABT-102 is a selective TRPV1 antagonist with robust efficacy in several preclinical models of pain. Three phase 1 studies evaluated ABT-102 pharmacokinetics upon oral administration to healthy human volunteers: a single-dose study (2, 6, 18, 30, and 40 mg) and a multiple-dose study (2, 4, and 8 mg twice daily for 7 days) using a solution formulation and a multiple-dose study (1, 2, and 4 mg twice daily for 7 days) using a solid-dispersion formulation. These studies followed double-blind, randomized, placebo-controlled designs. ABT-102 exhibited dose- and time-linear pharmacokinetics. ABT-102 half-life ranged from 7 to 11 hours, and steady state was achieved by day 5 of dosing. Population analysis of the pharmacokinetic data from the 3 studies was conducted. A 1-compartment model with a transit compartment for absorption and first-order elimination provided best fit to the data. The model included formulation-dependent lag times and a bioavailability factor (F(rel)) for solution relative to solid dispersion. The population parameter estimates (95% bootstrap confidence intervals) were oral clearance, 16 (14-18) L/h; oral volume of distribution, 215 (192-237) L; transit rate constant, 1.4 (1.3-1.6) h(-1); solid-dispersion lag, 0.6 (0.5-0.8) h; solution lag, 0.3 (0.2-0.4) h; and solution F(rel), 40% (35%-45%). Evaluation of ABT-102 pharmacokinetic model indicated its robustness and adequacy.
The safety of glycoprotein (GP) IIb/IIIa inhibitors has been well documented in clinical trials. Although these trials have included a broad patient population, the strict enrollment criteria may have resulted in exclusion of patients at a higher risk of bleeding complications. The authors conducted a retrospective chart review of 1020 consecutive patients who received GP IIb/IIIa inhibitors and underwent percutaneous coronary intervention in a large community hospital. They used Thrombolysis in Myocardial Infarction (TIMI) criteria to define major or minor bleeding complications. Bleeding complications developed in 214 (21%) patients, with major bleeding in 89 (9%). Univariate predictors of bleeding were older age, lower body weight, elevated serum creatinine, higher activated partial thromboplastin time (aPTT) level, history of diabetes mellitus (DM), peripheral vascular disease (PVD), congestive heart failure (CHF), and emergency procedure for acute myocardial infarction (AMI). Multivariate predictors of major bleeding were PVD (20% in bleeding group vs 11% in nonbleeders, odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2-2.6, P < .004), age (68 +/- 2 years, 95% CI = 66-70 in bleeding group vs 63 +/- 13 years, 95% CI = 61.2-63 in nonbleeders, P < .001), and higher aPTT level (66 +/- 27 seconds, 95% CI = 63-70 in bleeding group vs 53 +/- 28 seconds, 95% CI = 51-56 in nonbleeders, P < .001). The risk of bleeding in the large community hospital setting may be higher than in randomized clinical trials. This increased risk is associated with higher hospitalization costs. Recognition of predictors of bleeding should further enhance the safety of these antiplatelet agents.
Ecarin clotting time and activated partial thromboplastin time are coagulation tests that meet the definition of a biomarker. Prolongation of these coagulation times closely correlated with blood concentrations of the oral thrombin inhibitor LB-30057 (CI-1028) during a phase 1 study. But this simply reflects their functioning as enzyme inhibition assays of drug concentration. Directly adding the drug to blood results in the same concentration-response relationship. Changes in coagulation tests only demonstrate that ex vivo clot formation has been altered, not that an in vivo process has been affected. To be most informative in drug development, biomarker assays should measure in vivo drug effects, not drug concentrations.
5-Azacytidine was administered daily to 12 patients in a five-day schedule and to 15 patients in a weekly schedule as part of a phase I trial. The daily dose ranged from 50 mg/m2 to 158 mg/m2 and the weekly dose, from 200 mg/m2 to 633 mg/m2. The maximum total dose was 2000 mg in the daily schedule and 3775 mg in the weekly schedule. The major toxicity was gastrointestinal, with nausea and vomiting occurring in all patients in this study. Myelosuppression was less frequently encountered and appeared to be related to the increase in 5-azacytidine dose. Patients receiving 5-azacytidine in a weekly schedule of administration appeared to tolerate the drug better and to be more willing to continue their therapy.
The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.
The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.
The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).
Dabigatran etexilate (BIBR 1048) is an orally bioavailable double prodrug of the active principle dabigatran (BIBR 953 ZW), which exerts potent anticoagulant and antithrombotic activity. The objective of the analysis was to develop a population pharmacokinetic model characterizing and quantifying the relationship between covariates and model parameters. A total of 4604 BIBR 953 ZW plasma concentrations, obtained from 287 patients after once- or twice-daily oral dosing for up to 10 days after surgery in the dose range 12.5, 25, 50, 100, 150, 200, and 300 mg BIBR 1048, were available for the analysis. All the analyses were performed with NONMEN V. Pharmacokinetics of dabigatran were best described by a 2-compartment model. The data supported the estimation of different apparent first-order absorption rate constants (k(a)) and apparent plasma clearances (CL/F) for days 0 and 1 and days 2 to 10 after surgery. Parameter estimates indicated a flip-flop phenomenon. Age and serum creatinine influenced k(a), whereas gastrin and creatinine clearance, only for days 2 to 10, affected CL/F (P < .001). The typical values for CL/F for a patient with gastrin of 34.58 pmol/L and creatinine clearance of 76.16 mL/min were 70.87 and 106.2 L/h on days 0 and 1 and days 2 to 10, respectively. The differences found in the pharmacokinetics of dabigatran during the first 24 hours after surgery are most likely due to alterations in gastric motility and pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days, the disposition in plasma of BIBR 953 ZW is less variable.
Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ATR-107, a fully human monoclonal anti-IL-21 receptor (IL-21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo-controlled, double-blind trial in healthy subjects. The dose levels were 3-300 mg by SC and 30-120 mg by IV. The most important adverse events were hypersensitivity reactions occurring in 3 out of 6 subjects in 300 mg SC cohort and considered as dose limiting toxicity. More than 75% of the subjects who received ATR-107 developed anti-drug antibodies (ADAs), which had no discernible impact on PK or safety. The PK of ATR-107 appeared to be dose -proportional. T1/2 was shorter than typical therapeutic antibodies. Bioavailability of ATR-107 was about 30%. IL-21R occupancy was measured in circulating B cells in the 60 and 120 mg IV cohort. The data indicated that single dose of ATR-107 was able to maximally occupy IL-21Rs through at least Day 42. Further escalation in the FIH study was halted partially due to the high rates of ADA formation. In conclusion, ATR-107 had a prolonged PD effect measured by IL-21R occupancy; was highly immunogenic after single dose administration and had PK properties with rapid clearance and low bioavailability.
ABT-107 is a potent, selective α7 nicotinic receptor agonist under development for treatment of Alzheimer's disease and cognitive deficits associated with schizophrenia. The pharmacokinetics, safety, and tolerability of escalating single oral doses (1, 3, 10, 30, 60, 80, and 100 mg; double-blind, placebo-controlled, randomized, incomplete crossover design) and multiple oral doses (2, 6, and 15 mg once daily for 7 days; double-blind, placebo-controlled, randomized, parallel-group design) of ABT-107 were evaluated. Additionally, effect of food on ABT-107 pharmacokinetics (20-mg single dose) was evaluated using an open-label, 2-period, fasting and nonfasting, randomized, complete crossover design. ABT-107 exhibited nonlinear (more than dose-proportional) pharmacokinetics. ABT-107 half-life ranged from 7 to 10 hours, and steady state was achieved by day 6 of dosing. Food did not have a clinically meaningful effect on ABT-107 exposure. ABT-107 was safe and well tolerated over the tested dose range. The most frequently reported adverse events were nausea, headache, and tremor following single dosing and somnolence following multiple dosing. The pharmacokinetics, safety, and tolerability profiles of ABT-107 pose it as a good candidate for further development.