Search

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 (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).Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed., Areas Covered: This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed., Expert Opinion: The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.

Background: The small blood volume of mice complicates tacrolimus pharmacokinetic studies in these animals. Here we explored dried blood spot (DBS) as a novel method to measure tacrolimus blood concentrations in mice. DBS samples were collected from three sampling sites (cheek, tail and heart) and compared with heart whole blood samples measured via LC-MS/MS. Results: Tacrolimus concentrations in the whole blood samples ranged from 2.56 to 27.64 μg/l. DBS of cheek vein blood was the most reliable sampling site, with a mean bias of 0.15 μg/l (95% CI: -4.20 to 4.50). Conclusion: The DBS cheek method can be used for serial monitoring of tacrolimus blood concentrations in mice, offering an animal-friendly method for tacrolimus pharmacokinetic studies in mice.

Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgG-seronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed., (Copyright © 2021. Published by Elsevier Ltd.)

Aim: To investigate the association between donor CYP3A5 and ABCB1 polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients., Methods: The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors., Results: There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor-recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis., Conclusion: A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes.

Aims: Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. A potential cause may be differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA)., Methods: In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus. Patients were sampled repetitively, both before and during the first 6 months after kidney transplantation. Age-related variability in MPA PK, baseline IMPDH activity, as well as MPA-induced IMPDH inhibition were studied., Results: The IMPDH activity pre-transplantation did not differ between elderly and younger patients. Neither IMPDH activity pre-transplantation nor maximum IMPDH inhibition was significantly correlated with the patients' age. The area under the MPA plasma concentration-time curve (AUC 0-12h ) and the area under the effect (IMPDH activity)-time curve (AEC 0-12h ) from 0 to 12 h were also not significantly different between the two groups. We found no significant differences in EC 50 and E max between elderly and younger patients., Conclusions: Age did not significantly affect the PK or PD of MPA. It is unlikely that the lower incidence of acute rejection in elderly patients, or the higher risk to die from a severe infection in elderly patients is due to different handling of MPA in the elderly., (© 2016 The British Pharmacological Society.)

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., Competing Interests: T. van Gelder has received lecture fees from Chiesi Pharmaceuticals and Astellas Pharma B.V., and consulting fees from Astellas Pharma B.V., Novartis Pharma B.V., Roche Pharma, Teva Pharma and Sandoz Pharma. D.A. Hesselink has received lecture and consulting fees, as well as grant support from Astellas Pharma B.V., Bristol-Myers Squibb, Chiesi Pharmaceuticals, MSD Pharmaceuticals, Novartis Pharma B.V., and Roche Pharma. The other authors have no conflicts of interest to disclose. The authors declare no conflicts of interest.

Objectives: To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens., Methods: Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens., Results: AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily)., Conclusions: The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Real-time medication monitoring (RTMM) is a promising tool for improving adherence to inhaled corticosteroids (ICS), but has not been sufficiently tested in children with asthma. We aimed to study the effects of RTMM with short message service (SMS) reminders on adherence to ICS, asthma control, asthma-specific quality of life and asthma exacerbation rate; and to study the associated cost-effectiveness.In a multicentre, randomised controlled trial, children (aged 4-11 years) using ICS were recruited from five outpatient clinics and were given an RTMM device for 12 months. The intervention group also received tailored SMS reminders, sent only when a dose was at risk of omission. Outcome measures were adherence to ICS (RTMM data), asthma control (childhood asthma control test questionnaire), quality of life (paediatric asthma quality of life questionnaire) and asthma exacerbations. Costs were calculated from a healthcare and societal perspective.We included 209 children. Mean adherence was higher in the intervention group: 69.3% versus 57.3% (difference 12.0%, 95% CI 6.7%-17.7%). No differences were found for asthma control, quality of life or asthma exacerbations. Costs were higher in the intervention group, but this difference was not statistically significant.RTMM with tailored SMS reminders improved adherence to ICS, but not asthma control, quality of life or exacerbations in children using ICS for asthma., (Copyright ©ERS 2016.)

Background and Objective: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis., Methods: Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis., Results: The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates., Conclusions: Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients.

Introduction: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life., Areas Covered: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol)., Expert Opinion: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

Introduction: Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients., Areas Covered: Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated., Expert Opinion: First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.

Background: Many children with asthma do not have sufficient asthma control, which leads to increased healthcare costs and productivity loss of parents. One of the causative factors are adherence problems. Effective interventions improving medication adherence may therefore improve asthma control and reduce costs. A promising solution is sending real time text-messages via the mobile phone network, when a medicine is about to be forgotten. As the effect of real time text-messages in children with asthma is unknown, the primary aim of this study is to determine the effect of a Real Time Medication Monitoring system (RTMM) with text-messages on adherence to inhaled corticosteroids (ICS). The secondary objective is to study the effects of RTMM on asthma control, quality of life and cost-effectiveness of treatment., Methods: A multicenter, randomized controlled trial involving 220 children (4-11 years) using ICS for asthma. All children receive an RTMM-device for one year, which registers time and date of ICS doses. Children in the intervention group also receive tailored text-messages, sent only when a dose is at risk of omission. Primary outcome measure is the proportion of ICS dosages taken within the individually predefined time-interval. Secondary outcome measures include asthma control (monthly Asthma Control Tests), asthma exacerbations, healthcare use (collected from hospital records, patient reports and pharmacy record data), and disease-specific quality of life (PAQLQ questionnaire). Parental and children's acceptance of RTMM is evaluated with online focus groups and patient questionnaires. An economic evaluation is performed adopting a societal perspective, including relevant healthcare costs and parental productivity loss. Furthermore, a decision-analytic model is developed in which different levels of adherence are associated with clinical and financial outcomes. Also, sensitivity analyses are carried out on different price levels for RTMM., Discussion: If RTMM with tailored text-message reminders proves to be effective, this technique can be used in daily practice, which would support children with suboptimal adherence in their asthma (self)management and in achieving better asthma control and better quality of life., Trial Registration: Netherlands Trial Register NTR2583.

Background: Therapeutic 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., Objectives: The 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 (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients., Methods: A 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 AUC(12) 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 AUC(12) with the trapezoidal AUC(12)., Results: Tacrolimus 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 AUC(12). The bias was >20% in 1.8% of patients., Conclusion: Population 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.

Background and Objectives: The 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., Methods: In 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., Results: MPA 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., Conclusion: Lung 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.

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.

Aim: To investigate the differences in the pharmacokinetics of Prograf and the prolonged release formulation Advagraf and to develop a Bayesian estimator to estimate tacrolimus inter-dose area under the curve (AUC) in renal transplant patients receiving either Prograf or Advagraf., Methods: Tacrolimus concentration-time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation from 32 Prograf treated patients, and one profile was collected from 41 Advagraf patients more than 12 months post-transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations., Results: A two-compartment model with Erlang absorption (n= 3) and first-order elimination best described the data. In Advagraf patients, a bimodal distribution was observed for the absorption rate constant (K(tr) ): one group with a K(tr) similar to that of Prograf treated patients and the other group with a slower absorption. A mixture model for K(tr) was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3h post-dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%)., Conclusions: The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter-dose AUC in Prograf and Advagraf treated patients and is suitable for clinical practice., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

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.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.

Previous studies predicted that limited sampling strategies (LSS) for estimation of mycophenolic acid (MPA) area-under-the-curve (AUC(0-12)) 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 AUC(0-12) 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 AUC(0-12) for patients concurrently treated with cyclosporine was best estimated by AUC(0-12) (mg x h x L(-1)) = 36.536 + 1.642 x C0.5 + 0.569 x C1.5 + 0.905 x C2 (r2 = 0.33, bias = -1.0 mg x h x L(-1), precision = 24 mg x h x L(-1)), whereas AUC(0-12) [mg x h x L(-1)] = 19.801 + 1.827 x C0.5 + 1.111 x C1 + 1.429 x C2 was the best AUC(0-12) estimator for patients not cotreated with cyclosporine (r2 = 0.31, bias = 0.4 mg x h x L(-1), precision = 14.5 mg x h x L(-1)). Both LSS showed poor precision and overestimation of AUC(0-12) values below the therapeutic window and underestimation of AUC(0-12) 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 x h x L(-1). Estimation of MPA AUC(0-12) 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.

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 AUC(0-12) 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 AUC(0-12) 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 AUC(0-12) 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 AUC(0-12) 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.

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.

Treatment with the immunosuppressive agent mycophenolate mofetil (MMF) decreases the risk of rejection after renal transplantation and improves graft survival compared with azathioprine. The exposure to the active metabolite mycophenolic acid (MPA) is correlated to the risk of developing acute rejection. The interpatient variability in exposure of MPA is wide relative to the proposed therapeutic window of the MPA AUC(0 12) (30 - 60 mg.h/l). The pharmacokinetics of MPA are influenced by patient characteristics such as gender, time after transplantation, serum albumin concentration, renal function, comedication and pharmacogenetic factors. Therapeutic drug monitoring is likely to reduce inter-patient variability. Limited sampling strategies are used to predict the full AUC(0 12). Three prospective randomised studies compared concentration controlled MMF therapy to a fixed-dose regimen. Preliminary outcomes of these studies showed conflicting results and longer follow up is needed to further clarify the role of therapeutic drug monitoring in increasing the therapeutic potential of MMF.