Brenda C. M. de Winter

Pharmacokinetics of Mycophenolate mofetil in hematopoietic stem cell transplant recipients

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 μg*h/L (range: 56-411 μg*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.

Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure: Implications for Therapeutic Drug Monitoring

BACKGROUND AND OBJECTIVES 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 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. RESULTS 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. CONCLUSIONS MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.

Limited sampling strategies drawn within 3 hours postdose poorly predict mycophenolic acid area-under-the-curve after enteric-coated mycophenolate sodium

Previous studies predicted that limited sampling strategies (LSS) for estimation of mycophenolic acid (MPA) area-under-the-curve (AUC0-12) after ingestion of enteric-coated mycophenolate sodium (EC-MPS) using a clinically feasible sampling scheme may have poor predictive performance. Failure of LSS was thought to be due to the slow absorption of MPA causing late and variable times of maximum MPA concentration and variable predose concentrations. The aim of this study was to formally test the performance of LSS by developing and validating LSS for estimation of MPA AUC0-12 after EC-MPS administration. Pharmacokinetic data from 109 renal transplant recipients collected during the maintenance period after transplantation were analysed retrospectively. LSS were developed separately for renal transplant patients who concurrently used cyclosporine (n = 79) and for patients not concurrently treated with cyclosporine (n = 30). Data were split into an index and a validation data set. For clinical feasibility reasons, a LSS could consist of a maximum of 3 sampling time points with the latest sample drawn 2 hours after drug administration. LSS with the latest sample drawn 3 hours after drug administration or even later were also tested. The validation of the developed LSS showed that MPA AUC0-12 for patients concurrently treated with cyclosporine was best estimated by AUC0-12 (mg·h·L−1) = 36.536 + 1.642 × C0.5 + 0.569 × C1.5 + 0.905 × C2 (r2 = 0.33, bias = −1.0 mg·h·L−1, precision = 24 mg·h·L−1), whereas AUC0-12 [mg·h·L−1] = 19.801 + 1.827 × C0.5 + 1.111 × C1 + 1.429 × C2 was the best AUC0-12 estimator for patients not cotreated with cyclosporine (r2 = 0.31, bias = 0.4 mg·h·L−1, precision = 14.5 mg·h·L−1). Both LSS showed poor precision and overestimation of AUC0-12 values below the therapeutic window and underestimation of AUC0-12 values above the therapeutic window of MPA. Using C3 as latest sampling time point improved the fit slightly, but not satisfactory, with r2 still <0.40 and precision still >14.0 mg·h·L−1. Estimation of MPA AUC0-12 with LSS for EC-MPS drawn within 2 or 3 hours postdose in renal transplant recipients in the maintenance period is likely to result in biased and imprecise results.

Population pharmacokinetic modelling and design of a Bayesian estimator for therapeutic drug monitoring of tacrolimus in lung transplantation.

BackgroundTherapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome.ObjectivesThe aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC12) for its therapeutic drug monitoring in lung transplant recipients.MethodsA population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n= 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC12 on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC12 with the trapezoidal AUC12.ResultsTacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI — 1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC12. The bias was >20% in 1.8% of patients.ConclusionPopulation pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.

Limited sampling strategies for therapeutic drug monitoring of mycophenolate mofetil therapy in patients with autoimmune disease.

Mycophenolate mofetil (MMF) is increasingly used for the treatment of autoimmune diseases (AID). In renal transplant recipients, it has been demonstrated that adjustment of the MMF dose according to the area under the plasma concentration versus time curve (AUC) of mycophenolic acid (MPA), the active moiety of MMF, improves clinical outcome. The aim of this study was to develop a maximum a posteriori Bayesian estimator (MAP-BE) to estimate MPA AUC0-12 in patients with AID using a limited number of samples. The predictive performance of the MAP-BE was compared with a multiple linear regression method. Full MPA concentration versus time curves were available from 38 patients with AID treated with MMF. Nonlinear mixed-effect modeling was used to develop a population pharmacokinetic model. Patients were divided in an index and a validation data set. The pharmacokinetic model derived from the index data set was used to develop several MAP-BEs. The Bayesian estimators were used to predict AUC0-12 in the validation data set on the basis of a limited number of blood samples. The bias and precision of these predictions were compared with those of limited sampling strategies developed with multiple linear regression. The absorption of MPA was described with 2 first-order processes with a short and a long lag time and a subsequent first-order elimination. The 2-compartment model accounted for the enterohepatic recirculation of MPA as well. Using 1-4 samples, MPA AUC0-12 was adequately estimated by the MAP-BE. Bias (−5.5%) was not significantly different from zero, and precision was below 27%. The predictive performance of the multiple linear regression method was comparable. In conclusion, MAP-BEs were developed for the estimation of MPA AUC0-12 in patients with AID. The predictive performance was good and comparable to those of the multiple linear regression method. Due to its flexibility with respect to sample times, the MAP-BE may be preferred over the multiple linear regression method.

Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease.

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.

Bayesian Estimation of Mycophenolate Mofetil in Lung Transplantation, Using a Population Pharmacokinetic Model Developed in Kidney and Lung Transplant Recipients

Background and ObjectivesThe immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients.MethodsIn total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients’ profiles from the validation dataset.ResultsMPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p<0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p<0.001). The Bayesian estimator developed using the population pharmacokinetic model — and taking into account ciclosporin co-treatment, cystic fibrosis and time post-transplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration — resulted in a non-significant bias and mean imprecision of 5.8 mg • h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling.ConclusionLung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose

Background Bodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight. Methods For this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing. Results Data were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set. Conclusions This study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.