title: Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.
abstract: The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Abdelhady
authors.forename: Z
authors.initials: Z
authors.lastname: Desta
authors.forename: F
authors.initials: F
authors.lastname: Jiang
authors.forename: C W
authors.initials: CW
authors.lastname: Yeo
authors.forename: J G
authors.initials: JG
authors.lastname: Shin
authors.forename: B R
authors.initials: BR
authors.lastname: Overholser
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000465:Algorithms; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D003198:Computer Simulation; D018592:Cross-Over Studies; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000096:biosynthesis / Q000302:isolation & purification; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008954:Models, Biological; D010597:Pharmacogenetics; D011153:Population; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; C098320:efavirenz; D013988:Ticlopidine; C570209:8-hydroxyefavirenz
keywords: CYP2B6; efavirenz; metabolites; pharmacogenomics; pharmacokinetics