title: The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model.
abstract: OBJECTIVE
  Sirolimus is an mTOR inhibitor metabolized by CYP3A4 and CYP3A5. Reported effects of CYP3A5 polymorphisms on sirolimus pharmacokinetics (PK) have shown unexplained discrepancies across studies. We quantitatively assessed the effect of CYP3A5*3 status on sirolimus PK by in vitro assessment and simulation using a physiologically-based PK (PBPK) model. In addition, we explored designs for an adequately powered pharmacogenetic association study.
  
  
  METHODS
  In vitro metabolism studies were conducted to confirm individual CYP contribution to sirolimus metabolism. PK profiles were simulated in CYP3A5 expressers and non-expressers with a PBPK model. The pre-dose concentration predictions were used as the outcome parameter to estimate the required sample size for a pharmacogenetic association study.
  
  
  RESULTS
  Sirolimus metabolism was inhibited by over 90% by ketoconazole, a CYP3A specific inhibitor. The PBPK model developed based on CL(int) of recombinant CYP3A4, CYP3A5 and CYP2C8 predicted a small CYP3A5*3 effect on simulated sirolimus PK profiles. A subsequent power analysis based on these findings indicated that at least 80 subjects in an enrichment design, 40 CYP3A5 expressers and 40 non-expressers, would be required to detect a significant difference in the predicted trough concentrations at 1 month of therapy (P < 0.05, 80% power).
  
  
  CONCLUSIONS
  This study suggests that CYP3A5 contribution to sirolimus metabolism is much smaller than that of CYP3A4. Observed discrepancies across studies could be explained as the result of inadequate sample size. PBPK model simulations allowed mechanism-based evaluation of the effects of CYP3A5 genotype on sirolimus PK and provided preliminary data for the design of a future prospective study.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati.|Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati.
authors.forename: Raja
authors.initials: R
authors.lastname: Venkatasubramanian
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati.|Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D020123:Sirolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus
keywords: CYP3A4; CYP3A5*3 polymorphism; PBPK model; sirolimus