Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

Abstract

A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n ‫؍‬ 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.

Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

“…This study complements our previously published report (9) in which we investigated the influence of CYP2B6, CYP3A4, and MDR1 genotypes on EFV kinetics in 32 patients and obtained a final model in which only the effect of the CYP2B6 516G3T polymorphism had an influence on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%.…”

“…In particular, the single nucleotide polymorphism (SNP) CYP2B6 516G3T has been reported to be significantly associated with a pronounced reduction in enzyme activity and elevated EFV plasma concen-trations in studies conducted on different populations (1, 9, 11, 15, 20, 24, 31-33, 35, 36, 38, 44, 47, 49, 50, 57). Thus, patients showing G/T and T/T CYP2B6 polymorphisms exhibited EFV clearances that were about 50% and 75% lower than those observed in patients without these polymorphisms (G/G) (9). More recently, the SNPs CYP2B6 983T3G and 785A3G were also reported to affect EFV plasma concentrations (20,21,33,44,49,50,59).…”

“…However, although population PK analyses on EFV have been reported in the literature (1,9,13,36,42), only some of these have integrated PG information (1,9,36).…”

“…Therefore, estimated fixed-effect PK parameters included the apparent clearance (CL/F) and the apparent distribution volume (V/F). Both additive and exponential error models were tested to explain interindividual and residual variability, as described in our previous study (9).…”

CYP2B6 18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying CYP2B6 Haplotype *1/*1

“…The consideration of a minimum concentration of 1 mg/ liter was based upon an acceptable 70% treatment response rate (15), whereas Stahle and colleagues suggested raising that minimum to achieve at least an 80% response rate (20). Previous studies have shown that patients who had low or subtherapeutic efavirenz concentrations had an increased chance for the development of HIV-resistant strains and subsequent treatment failure (15,21,22). Moreover, efavirenz has a low genetic barrier to resistance; in fact, a single mutation results in high-level resistance to not only efavirenz but also to other drugs in the same class (23).…”