Individualisation of Mycophenolate Mofetil Therapy: Explaining variability in mycophenolic acid pharmacokinetics and introducing therapeutic

The prodrug mycophenolate mofetil contains the active compound mycophenolic acid (MPA), which has immunosuppressive properties. It is used to prevent acute rejection after solid organ transplantation. In renal transplantation, the dose recommendation for mycophenolate mofetil is 1000 mg twice daily for adult patients. This fixed dose strategy for mycophenolate mofetil is remarkable in the field of transplantation as most other immunosuppressive drugs are used in an individualised dose, often based on drug concentration measurements. During the use of mycophenolate mofetil in the past ten years, data have become available which provide four reasons to question the justification of a fixed mycophenolate mofetil dose. The first reason is the existence of a concentration-effect relationship: the risk for acute rejection is lower when exposure to MPA is higher. This has led to the adoption of a target exposure range for MPA area-under-the-curve (AUC0-12) values of 30 to 60 mg*h/L. The second reason is the large between-patient variability in MPA pharmacokinetics, reported to be more than 10-fold for MPA AUC0-12. The third reason is that MPA exposure increases over time after transplantation despite a fixed dose. Finally, exposure to MPA is significantly influenced by the use of several other drugs. The result of these four factors is that with the use of a standard dose of mycophenolate mofetil, an important subset of renal transplant recipients will have MPA exposure outside the target range, and may therefore be at risk for acute rejection or toxicity. Individualisation of the mycophenolate mofetil dose is likely to improve exposure to MPA and may optimise clinical outcome. The aim of this thesis was to develop recommendations about when and how to individualise the mycophenolate mofetil dose. Two hypotheses in this regard were addressed, formulated in c

Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reprodu

Population pharmacokinetics of mycophenolic acid in renal transplant recipients

Background: Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics. Objective: The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters. Patients and methods: Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling. Results: The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (ka) 4.1h -1, central volume of distribution (V1) 91L, peripheral volume of distribution (V2) 237L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21h. The interpatient variability for ka, V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for ka, V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001). Conclusion: The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated