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ABSTRACT: High intra-patient variability in TCL exposure is a risk factor for allograft loss and late acute rejection. We hypothesized that a higher intra-patient variability leads to a faster decline in GFR in pediatric renal transplant patients and that adolescents have a higher intra-patient variability due to poorer adherence. We included 69 children aged 3.5-18 yr who had undergone renal transplantation between April 1996 and May 2009 in two pediatric nephrology centers in the Netherlands. We analyzed TCL trough concentrations over a period of one yr and calculated TCL trough concentrations variability using VC. We investigated the correlation between the TCL trough concentrations variability and the decline in estimated GFR over four yr. The median intra-patient variability in TCL concentrations was 30.1% (range 8.6-77.6) and the mean GFR slope -3.8 mL/min/1.73 m(2) /yr. The VC correlated neither with the GFR slope, nor with the patients' age. However, children with late acute rejection had higher VC (p = 0.045). We were unable to provide evidence that a high variability in TCL exposure leads to a faster decline in renal function, although children with late acute rejection have a higher variability in TCL exposure. Adolescents do not have a higher intra-patient variability in TCL trough concentrations than younger children.
Pediatric Transplantation 06/2012; 16(6):613-8. · 1.48 Impact Factor
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ABSTRACT: Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PK-guided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure.
A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing.
Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%.
Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity.
Clinical Cancer Research 01/2011; 17(2):353-62. · 7.74 Impact Factor
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ABSTRACT: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies.
Retrospective analysis.
Level III pediatric intensive care unit.
Two pediatric patients with myopathies and acute liver failure. CLINICAL INVESTIGATIONS: We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method for drug-induced liver injury to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies.
The serum adduct levels were consistent with the values previously reported in children with acute liver injury following acetaminophen overdose. We found four similar cases of acute liver failure in pediatric and adult patients with myopathies following recommended acetaminophen doses in the literature (n = 3) and personal communication (n = 1). The Roussel Uclaf Causality Assessment Method suggested a probable relationship between acetaminophen use at recommended doses and acute liver failure in our myopathy patients.
Our data suggest that some patients with myopathies who are receiving recommended doses of acetaminophen may be at increased risk for the development of toxicity resulting in acute liver failure. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking acetaminophen, especially when critically ill or postoperative.
Critical care medicine 01/2011; 39(4):678-82. · 6.37 Impact Factor
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ABSTRACT: Pediatric pharmacokinetic studies require sampling of biofluids from neonates and children. Limitations on sampling frequency and sample volume complicate the design of these studies. In addition, strict guidelines, designed to guarantee patient safety, are in place. This chapter describes the practical implications of sample collection and their storage, with special focus on the selection of the appropriate type of biofluid and withdrawal technique. In addition, we describe appropriate measures for storage of these specimens, for example, in the context of biobanking, and the requirements on drug assay methods that they pose. Pharmacokinetic studies in children are possible, but they require careful selection of an appropriate sampling method, specimen volume, and assay method. The checklist provided could help prospective researchers with the design of an appropriate study protocol and infrastructure.
Handbook of experimental pharmacology 01/2011; 205:203-17.
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ABSTRACT: Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg·h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated.
MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n = 140) or tacrolimus (n = 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated.
In the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (=100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P < 0.001); respective values in tacrolimus-cotreated patients were 176%, 133%, 85%, and 76% (P < 0.001). Because of the decreasing relative bioavailability, MPA exposure will increase less than proportionally with increasing MMF doses.
MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.
Clinical Journal of the American Society of Nephrology 11/2010; 6(3):656-63. · 5.23 Impact Factor
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ABSTRACT: For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.
Therapeutic drug monitoring 10/2010; 32(5):606-14. · 2.43 Impact Factor
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ABSTRACT: Midazolam is used to sedate children during extracorporeal membrane oxygenation (ECMO). Pharmacokinetic changes are expected because of extracorporeal circulation and maturation. We present a population pharmacokinetic model for midazolam and its major metabolites in neonates during venoarterial ECMO.
We studied 20 neonates on venoarterial ECMO, with a median postnatal age of 0.79 (range 0.17-5.8) days and a bodyweight of 3.0 (range 2.7-3.9) kg at the onset of ECMO. The median ECMO duration was 124 (range 70-275) hours. Serum concentrations were measured at the initiation and discontinuation of the midazolam infusion (100-300 microg/kg/h). Analysis of concentrations of midazolam, 1-hydroxymidazolam and its glucuronide were performed using nonlinear mixed-effects modelling. A two-compartment model for midazolam and a one-compartment model for the metabolites 1-hydroxymidazolam and hydroxymidazolam glucuronide adequately described the data, with allometric scaling of all parameters.
Following the start of ECMO, the volume of distribution of midazolam increased from 4.29 to 14.6 L/3 kg, with an elimination half-life of 1.85 hours. The median midazolam and 1-hydroxymidazolam clearance values increased 3-fold within the first 5 days (up to 1.38 and 5.31 L/h/3 kg, respectively), whereas hydroxymidazolam glucuronide clearance remained constant at 0.18 L/h/3 kg. Interpatient variability estimates of midazolam, 1-hydroxymidazolam and hydroxymidazolam glucuronide clearance and midazolam and hydroxymidazolam glucuronide volumes of distribution varied between 87% and 129%. Concomitant inotropic infusion increased hydroxymidazolam glucuronide clearance by 23%.
After allometric scaling, clearance of midazolam and 1-hydroxymidazolam increases as a result of maturation or recovery from critical illness. In ECMO patients weighing 2.7-3.9 kg, continuously infused midazolam doses of 300 microg/kg/h for 6 hours and 150 microg/kg/h thereafter provide adequate serum concentrations for sedation. The dose must be increased substantially after 5-7 days. Hydroxymidazolam glucuronide accumulates during ECMO, providing an increased proportion of the overall effect, up to 34% after 7 days. Large unexplained interpatient variability warrants careful titration of sedation and adverse effects.
Clinical Pharmacokinetics 06/2010; 49(6):407-19. · 5.40 Impact Factor
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ABSTRACT: We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation.
From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used.
In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure.
This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.
Nephrology Dialysis Transplantation 02/2010; 25(8):2757-63. · 3.40 Impact Factor
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ABSTRACT: A sensitive and specific method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of levetiracetam (LEV) in plasma of neonates. A plasma aliquot of 50 microl was deproteinized by addition of 500 microl methanol which contained 5 microg/ml UCB 17025 as an internal standard. After centrifugation, 50 microl of supernatant was diluted with 1000 microl of 0.1% formic acid-10 mM ammonium formate in water (pH 3.5) (mobile phase solution A) and 2 microl was injected onto the UPLC-system. Compounds were separated on a Acquity UPLC BEH C(18) 2.1 mm x 100 mm column using gradient elution with mobile phase solution A and 0.1% formic acid in methanol (mobile phase solution B) with a flow rate of 0.4 ml/min and a total runtime of 4.0 min. LEV and the internal standard were detected using positive ion electrospray ionization followed by tandem mass spectrometry (ESI-MS/MS). The assay allowed quantification of LEV plasma concentrations in the range from 0.5 microg/ml to 150 microg/ml. Inter-assay inaccuracy was within +/-2.7% and inter-assay precision was less than 4.5%. Matrix effects were minor: the recovery of LEV was between 97.7% and 100%. The developed method required minimal sample preparation and less plasma sample volume compared to earlier published LC-MS/MS methods. The method was successfully applied in a clinical pharmacokinetic study in which neonates received intravenous administrations of LEV for the treatment of neonatal seizures.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 01/2010; 878(7-8):675-81. · 2.78 Impact Factor
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ABSTRACT: To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH).
We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics.
A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml.
SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.
Archives of Disease in Childhood - Fetal and Neonatal Edition 11/2009; 95(2):F109-14. · 3.05 Impact Factor
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ABSTRACT: At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.
Antimicrobial Agents and Chemotherapy 03/2009; 53(5):2005-13. · 4.84 Impact Factor
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ABSTRACT: Renal function and the plasma albumin concentration have been shown to correlate with clearance of total mycophenolic acid (MPA). The hypothesis for the underlying mechanism is that low plasma albumin concentrations and accumulation of the glucuronide metabolite of MPA (MPAG) decrease the binding of MPA to albumin. The subsequent increase in the unbound fraction (f(u)) of MPA (MPA(u)) produces an increase in total MPA (MPA(t)) clearance. This study aimed to develop an empirical population pharmacokinetic model to describe the relationships between renal function and albumin concentration and MPAG, MPA(u) and MPA(t), in order to provide insight into the mechanism by which renal function and plasma albumin affect the disposition of MPA.
774 MPA(t), 479 MPA(u) and 772 total MPAG (MPAG(t)) plasma concentrations were available from 88 renal transplant recipients on days 11 and 140 after transplantation. Data were analysed using non-linear mixed-effects modelling.
Time profiles of MPA(u) and MPAG(t) concentrations were adequately described by two 2-compartment pharmacokinetic models with a link between the central compartments, representing the glucuronidation of MPA(u) to form MPAG. MPA(t) concentrations were modelled using: [MPA(t)] = [MPA(u)] + [MPA(u)] * theta(pb), with [MPA(u)] * theta(pb) representing the bound MPA concentration, where [MPA(t)], [MPA(u)] and theta(pb) represent MPA(t) concentration, MPA(u) concentration and a factor that correlates to the total number of protein binding places, respectively. According to this equation, f(u) = [MPA(u)]/[MPA(t)] = 1/(1 + theta(pb)) * theta(pb), and therefore [MPA(t)], was significantly and independently correlated with creatinine clearance (CL(CR)), the plasma albumin concentration and the MPAG(t) concentration (all p < 0.001). A reduction in CL(CR) from 60 to 25 mL/min correlated with an increase in f(u) from 2.7% to 3.5%, accumulation of MPAG(t) concentrations from 50 to 150 mg/L correlated with an increase in f(u) from 2.8% to 3.7%, and a decrease in plasma albumin concentration from 40 to 30 g/L correlated with an increase in f(u) from 2.6% to 3.5%. No significant correlations were detected between MPA(u) clearance and the plasma albumin concentration or CL(CR).
The model shows that low CL(CR), low plasma albumin concentrations and high MPAG concentrations decrease MPA(t) exposure by affecting MPA binding to albumin.
Clinical Pharmacokinetics 01/2009; 48(7):463-76. · 5.40 Impact Factor
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ABSTRACT: The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study.
During surgery all infants (6 months-2 years) received a rectal loading dose of 40 mg.kg(-1) paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg.kg(-1) propacetamol, a prodrug of paracetamol, or 20 mg.kg(-1) paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0-10 cm) and COMFORT Behavior scale (score 6-30) were used to monitor analgesia in the 24-h period following surgery.
Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric '1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l.h(-1).70 kg(-1), intercompartmental clearance 116 l.h(-1).70 kg(-1), central and peripheral volume of distribution 7.9 and 44 l.70 kg(-1), respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score >/=4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05).
Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain.
Pediatric Anesthesia 07/2008; 18(7):582-92. · 2.10 Impact Factor
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ABSTRACT: A high-dose-step-down strategy for caspofungin treatment was evaluated in an experimental model of advanced-stage invasive pulmonary aspergillosis. The therapeutic efficacy of caspofungin in relation to the severity of invasive pulmonary infection caused by Aspergillus fumigatus in transiently neutropenic rats was investigated by using rat survival and the decrease in the fungal burden as the parameters of efficacy. When treatment was started at either 16 h or 24 h after fungal inoculation, caspofungin administered intraperitoneally at 4 mg/kg of body weight/day for 10 days was highly effective (100% and 93% rat survival, respectively). However, only 27% rat survival was obtained when treatment was started at 72 h, when the rats had advanced-stage infection. Increasing the dose from 4 to 10 mg/kg/day could compensate for the decrease in efficacy and resulted in 67% rat survival. The high dose of 10 mg/kg/day for 10 days did not appear to be necessary since a high-dose-step-down dosing schedule with 10 mg/kg/day for 3 days followed by 4 mg/kg/day for 7 days was equally effective. At 10 days after the end of treatment with 10 mg/kg/day caspofungin, the level of neither A. fumigatus DNA nor A. fumigatus galactomannan in the infected left lung was significantly decreased. In contrast, A. fumigatus galactomannan concentrations in serum were significantly decreased. The levels of creatinine, blood urea nitrogen, alanine aminotransferase, and asparate aminotransferase were not elevated during treatment. Caspofungin is effective for the treatment of invasive pulmonary aspergillosis in transiently neutropenic rats and is even effective in rats with advanced-stage infection. In this model, the administration of high-dose-step-down treatment was as effective as treatment with high doses for the whole treatment period.
Antimicrobial Agents and Chemotherapy 05/2008; 52(4):1345-50. · 4.84 Impact Factor
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Brenda C M de Winter,
Teun van Gelder,
Petra Glander,
Dario Cattaneo,
Helio Tedesco-Silva,
Irmgard Neumann,
Luuk Hilbrands,
Reinier M van Hest,
Mark D Pescovitz,
Klemens Budde, Ron A A Mathot
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ABSTRACT: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).
MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM). A two-compartment model with first-order absorption and elimination was used to describe the data.
No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h(-1) and 4.1 h(-1) (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (t(lag)) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the t(lag) values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning t(lag) following EC-MPS administration was significantly different from both the t(lag) following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the t(lag) following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the t(lag) was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r(2) = 0.02) than in MMF-treated patients (r(2) = 0.48).
Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the t(lag) varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.
Clinical Pharmacokinetics 02/2008; 47(12):827-38. · 5.40 Impact Factor
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Brenda C.M. de Winter,
Teun van Gelder,
Petra Glander,
Dario Cattaneo,
Helio Tedesco-Silva,
Irmgard Neumann,
Luuk Hilbrands,
Reinier M. van Hest,
Mark D. Pescovitz,
Klemens Budde, Ron A.A. Mathot
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ABSTRACT: Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM®). A two-compartment model with first-order absorption and elimination was used to describe the data.Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h−1 and 4.1 h−1 (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (tlag) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the tlag values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning tlag following EC-MPS administration was significantly different from both the tlag following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the tlag following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r2 = 0.02) than in MMF-treated patients (r2 = 0.48).Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the tlag varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.
Clinical Pharmacokinetics 12/2007; 47(12):827-838. · 5.40 Impact Factor
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ABSTRACT: The anticancer drug docetaxel is extensively metabolized by cytochrome P450 (CYP) 3A isozymes. Furthermore, docetaxel is also a substrate for the transmembrane ATP-binding cassette efflux transporter protein ABCB1. CYP3A-inhibition significantly reduces docetaxel total systemic clearance, on average by 50%. However, data on the effect of CYP3A-inhibition on the fecal and urinary excretion of docetaxel are lacking. To further elucidate the role of CYP3A- and ABCB1-mediated elimination pathways for docetaxel we investigated the effect of the potent CYP3A-inhibitor, and also ABCB1-inhibitor, ketoconazole on the fecal and urinary disposition of docetaxel in cancer patients.
Fifteen patients were treated with docetaxel (100 mg/m2), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [3H]-radiolabeled docetaxel. Fecal and urinary specimens, collected up to 72-h post-infusion, were analyzed for cumulative parent drug and radioactivity excretion.
Ketoconazole coadministration increased fecal parent drug excretion twofold from 2.6 +/- 2.8 to 5.2 +/- 5.4% (mean +/- SD, P = 0.03) but did not affect urinary parent drug excretion (P = 0.69). The sum of fecal and urinary parent drug excretion was 5.3 +/- 3.0% for docetaxel alone and 7.8 +/- 5.6% in the presence of ketoconazole, respectively (P = 0.04). Total recovered radioactivity values were 45.8 +/- 19.1 and 32.4 +/- 19.7%, respectively (P = 0.23).
CYP3A-inhibition by ketoconazole increases fecal parent drug excretion twofold in cancer patients. A more pronounced increase was not achieved, most likely due to concomitant intestinal ABCB1-inhibition.
Cancer Chemotherapy and Pharmacology 10/2007; 60(4):569-79. · 2.83 Impact Factor
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ABSTRACT: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 microg*h/L (range: 56-411 microg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.
Therapeutic Drug Monitoring 07/2007; 29(3):353-60. · 2.49 Impact Factor
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ABSTRACT: To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation.
Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis.
Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively).
Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments.
The Oncologist 04/2007; 12(3):291-300. · 3.91 Impact Factor
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ABSTRACT: The anticancer drug docetaxel (Taxotere) is formulated in the nonionic surfactant polysorbate 80 (Tween 80). Early in the clinical development of docetaxel, it became clear that docetaxel administration is associated with the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. These side-effects have been attributed, in part, to the presence of polysorbate 80 and have consequently initiated research focused on the development of a less-toxic, better-tolerated polysorbate 80-free formulation of docetaxel. More recently, there is an increasing interest in developing a (polysorbate 80-free) docetaxel formulation that selectively targets malignant tissue, thereby increasing efficacy while decreasing the occurrence of side-effects related to wide and nonspecific body distribution. This review aims to discuss the preclinical and clinical results of pharmaceutical strategies [PEGylated (immuno)liposomal docetaxel, docetaxel-fibrinogen-coated olive oil droplets, docetaxel encapsulated nanoparticle-aptamer bioconjugates, submicronic dispersion formulation] to develop an alternative, solvent-free, delivery form for docetaxel characterized by increased efficacy and decreased toxicity.
Anti-Cancer Drugs 03/2007; 18(2):95-103. · 2.41 Impact Factor
