title: Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients.
abstract: OBJECTIVE
  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, we selected clinically relevant covariates considering covariate effects. 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 (n=34), 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 AUC0-12h in the 30-60 mg.h/L.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Han
authors.forename: Hwi-yeol
authors.initials: HY
authors.lastname: Yun
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Oh
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D003198:Computer Simulation; D003404:Creatinine / Q000097:blood / Q000652:urine; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017711:Nonlinear Dynamics; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D013608:Tablets, Enteric-Coated; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013608:Tablets, Enteric-Coated; C000715591:UGT1A9 protein, human; D003404:Creatinine; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D009173:Mycophenolic Acid