Supervisors info:
Αριστείδης Δοκουμετζίδης, Επίκουρος Καθηγητής Τμήματος Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Mycophenolic acid (MPA) is the first-line antiproliferative agent, which is used as a maintenance immunosuppressive therapy, after renal transplantation. There are two formulations of MPA: Mycophenolate Mofetil (MMF), which is an ester (CellCept®), and enteric-coated mychophenolate sodium (EC-MPS, (Myfortic®)).
The aim of this study is to characterize the pharmacokinetics of MPA and to describe the differences between the two formulations. Therefore, MPA concentration-time profiles were obtained from 173 patients. Patients were divided into two groups, depending on the MPA formulation they received. For each group, a population pharmacokinetic model was developed, in order to simulate optimally the observed data. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM® version 7.3.) For the estimation of the population values of the parameters was chosen the IMPMAP method and for the individualized parameter values the POSTHOC command.
A two-compartment model with first order absorption and first order elimination was found adequate to describe the data for both MPA formulations. Interindividual variability for each pharmacokinetic parameter was expressed using an exponential error model. However, Interindividual variability of the intercompartmental clearance (Q) of EC-MPS was set zero, in order to optimize the simulation of the model to the observed data. Residual variability was described using a proportional error model. Typical values for the pharmacokinetic parameters: CL, V2, V3, Q, Ka and tlag ( tlag was estimated only for EC-MPS) were estimated. Since bioavailability (F) could not be quantified, CL, V2, V3 and Q values of MPA corresponded to the ratios CL/F, V2/F, V3/F and Q/F, respectively. Moreover, the influence of covariates, such as age, weight and creatinine clearance, on the pharmacokinetic parameters was evaluated. Only the weight was found to reduce significantly the Interindividual variability of drug clearance for both formulations. Final model adequacy was evaluated by using goodness-of-fit plots and objective function value. Then, it was further validated with Bootstrap and VPC internal validation methods.
Based on the final model, it was possible to estimate the individualized parameters and calculate the patient's AUC0-12h. AUC0-12h target range is 30-60mg * h / L for kidney transplantation. However, AUC values revealed that 62% and only 39% of patients receiving MMF and EC-MPS, respectively, were within the therapeutic range. It is obvious that fix dosages are not suitable for all the patients. In addition, the results highlight the importance of dose optimization in order to avoid graft rejection and toxicity. Thus, for all the patients, whose AUC0-12h was found out of the therapeutic range, an individualized dose was calculated, targeting therapeutic blood levels of MPA. Also, an easy way to choose the most suitable dosage of MMF and EC-MPS was proposed, depending on the value of drug clearance estimated by the model for each patient.
Keywords:
Mycophenolic acid, population pharmacokinetics,NONMEM, CellCept, Myfortic
