Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil. (6th April 2013)

• Record Type: Journal Article
• Authors: Li, H.; Mager, D.E.; Sandmaier, B.M.; Maloney, D.G.; Bemer, M.J.; McCune, J.S.
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 4(2013:Apr.)
• Page Start: 393
• Page End: 402
• Publication Date: 2013-04-06
• Subjects: dosing simulation -- hematopoietic cell transplantation -- limited sampling schedule -- mycophenolic acid -- population pharmacokinetics; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.14
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety‐six MPA concentration–time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two‐compartment model with first‐order elimination and a time‐lagged first‐order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five‐sample LSS and maximum a posteriori Bayesian estimation.