Population Pharmacokinetics Of Mycophenolic Acid Research Articles

Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation

To investigate the population pharmacokinetics of mycophenolic acid (MPA) in adult kidney transplant recipients during the crucial first week after transplantation. Data were collected from 117 patients. MPA plasma concentrations were determined at t=0, 1, 2, 3 and 4 h after mycophenolate mofetil dosing on days 3, 5 and 7. Population analysis was performed using NONMEM. Covariates screened were sex, age, body weight, serum creatinine, creatinine clearance, serum albumin, days of therapy, diabetes mellitus, organ source (live or cadaveric) and co-therapy (tacrolimus or cyclosporine). Final model validity was evaluated using 200 boot strapped samples from the original data. Bias and precision were determined through comparison of observed and predicted concentrations. Individual concentration-time profiles showed evidence of an absorption lag time and enterohepatic recirculation of MPA in some patients on some occasions. The best base model had bi-exponential elimination with a typical population (SE%) apparent clearance (CL/F) of 29 l/h (5%) and apparent volume of the central compartment of 65 l (7%). CL/F decreased significantly with increasing serum albumin (1.42 l/h reduction in total plasma CL/F with each 1 g/l increase in albumin) and was 27% greater in patients receiving cyclosporine than in those receiving tacrolimus. Evaluation of the final model showed close agreement between pairs of boot strapped and final model parameter estimates (all differences <7%). Predictions were non-biased (0.11 mg/l) but imprecise (2.8 mg/l). Population pharmacokinetic parameters for MPA were determined. These can be used to achieve specific target MPA concentrations or areas under the concentration-time curve.

Population Pharmacokinetics of Mycophenolic Acid in Kidney Transplant Pediatric and Adolescent Patients

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients

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. 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. 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. 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 (k(a)) 4.1h(-1), central volume of distribution (V1) 91 L, peripheral volume of distribution (V2) 237 L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21 h. The interpatient variability for k(a), V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for k(a), 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). 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.