title: Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition.
abstract: Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6 While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero- and first-order processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.).
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.
authors: Jason D
authors: JD
authors: Robarge
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.
authors: Ingrid F
authors: IF
authors: Metzger
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.
authors: Jessica
authors: J
authors: Lu
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.
authors: Nancy
authors: N
authors: Thong
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.
authors: Todd C
authors: TC
authors: Skaar
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA zdesta@iu.edu.
authors: Zeruesenay
authors: Z
authors: Desta
authors: Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, USA.|State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.
authors: Robert R
authors: RR
authors: Bies
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000493:pharmacokinetics*; D001711:Biotransformation; D015992:Body Mass Index; D001835:Body Weight; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics* / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012737:Sex Factors; D014018:Tissue Distribution
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: body composition; cytochrome P450 2B6 (CYP2B6); efavirenz; population pharmacokinetics