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 firstorder 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.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…The CL/F estimates of EFV for individuals with the CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6 genotypes were 18, 14, and 8.6 liters/h, respectively. This finding highlights the growing literature evidence that warrants a pharmacogeneticsbased dose adjustment for EFV (3,5,22,31).…”

“…PK models describing the disposition of efavirenz in plasma have been reported previously (3,(10)(11)(12)(13). A single study reported a PK model comprising both the parent drug (EFV) and the metabolite (8OHEFV) in plasma after a single dose that was lower than the recommended dose of efavirenz in 17 healthy Korean male subjects (14).…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…Based on current evidence ( Table ), CYP2B6 normal metabolizers (NMs) are expected to have normal efavirenz metabolism and achieve therapeutic efavirenz concentrations with standard dosing (600 mg/day). CYP2B6 IMs may experience higher dose‐adjusted trough concentrations compared with NMs, which may put these patients up to a 1.3‐fold increased risk of adverse effects . For these patients, there is a “moderate” recommendation to consider initiating efavirenz with a decreased dose of 400 mg/day.…”

Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants

“…The effect of genotypic differences on efavirenz concentrations, as well as the allele frequency of the major metabolizing enzyme in different race and ethnicity groups, has been described previously. 6–8 Population pharmacokinetic modeling has shown that weight and fat-free mass affect the clearance of efavirenz; however, the association of sex with concentration differences appears to be inconclusive. 8–10 …”

“…6–8 Population pharmacokinetic modeling has shown that weight and fat-free mass affect the clearance of efavirenz; however, the association of sex with concentration differences appears to be inconclusive. 8–10 …”