Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach

Abstract

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

“…A total of 11 popPK models of MMF co‐administered with TAC were included for external evaluation after the literature retrieval. The details of the literature search process are provided in Appendix S1.…”

“…Among them, seven were multicentre studies and four were single‐centre studies . Although >60% of the included models were conducted in multicentres, the sample size of kidney transplant recipients co‐administered with TAC was >100 in only one study , and 50–100 in two . In addition, only one study was conducted in Chinese individuals while the remaining 10 were mainly conducted in Caucasians.…”

“…Furthermore, both intensive and sparse samples were collected in five studies , only intensive samples were collected in three , and only sparse samples were obtained in the other three studies . Samples were obtained within 1 month post‐operation in two studies , and 1–204 months post‐operation in another study . Moreover, samples collected within and after the first month post‐operation were simultaneously included in the remaining eight studies .…”

“…The structural models adopted were either conventional two‐compartment (2CMT) models or 2CMT models with an EHC process . BSV was modelled using an exponential model.…”

“…To characterize MPA PK, four studies used first‐order absorption, while the other seven studies incorporated absorption lag time (Tlag) with first‐order absorption. Conventional 2CMT models were used in seven studies and 2CMT models with an EHC process were employed in the other four studies . EHC processes were modelled to be continuous in two studies and intermittent in the other two studies .…”