Nayoung Han(1), Hwi-yeol Yun(1), In-Wha Kim(2), Yoon Jung Oh(3), Yon Su Kim(4), Jung Eben(1), Yoo younghoon(1), Jung Mi Oh(2)*
(1) College of Pharmacy, Chungnam National University, Korea; (2) College of Pharmacy, Seoul National University, Korea; (3) Department of Internal Medicine, Cheju Halla General Hospital, Korea; (4) Department of International Medicine, College of Medicine, Seoul National University, Korea
Objectives: Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients.
Methods: Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method (SCM), we selected clinically relevant covariates considering covariate effects and covariates were identified by using bootstrap analyses of the SCM. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios.
Results: From 166 plasma concentrations in 34 patients, a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC(0-12h) in the 30-60 mg.h/L.
Conclusions: In conclusion, CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.
Reference: PAGE 25 () Abstr 5742 [www.page-meeting.org/?abstract=5742]
Poster: Drug/Disease modeling - Other topics