Intra-Individual Variability in Efavirenz Plasma Concentrations Supports Therapeutic Drug Monitoring Based on Quarterly Sampling in the First Year of Therapy

Abstract

Intrapatient variability in drug plasma concentrations is critical to the use of therapeutic drug monitoring with efavirenz, a non-nucleoside reverse-transcriptase inhibitor. Marked intrapatient variability, particularly for concentrations near the minimal therapeutic concentration, could be a predictor of virologic failure, meaning that a single concentration is of limited value. Previous reports on efavirenz intra-individual variability were obtained only in follow-up periods of 3 to 12 months and do not provide a rationale for the periodicity of sample measurements needed in long-term therapy to identify patients with a large variability and increased risk of therapeutic failure. The aim of this work was to investigate intra-individual variability in efavirenz plasma concentrations over a long-term follow-up period to support therapeutic drug monitoring. In a case series study, clinical and laboratory data were collected from all HIV-positive adults at the immunodeficiency outpatient clinic who were on regimens containing efavirenz in 2002 and who gave their informed consent (n = 31). Efavirenz plasma concentrations were measured throughout a 3 year period, without dose adjustments. For each patient, 6 to 12 samples were obtained over the follow-up period with an interval of at least 3 months between each sample. Mean plasma concentrations (mg/L) in the first, second, and third year of follow-up were 2.20 +/- 0.64, 2.17 +/- 0.68, and 2.31 +/- 0.57. Mean intra-individual variability throughout the first, second, and third year of study was 27%, 31%, and 25%, ranging from 12% to 63%. No differences in intrapatient variability in efavirenz plasma concentrations were found between females and males, HBV/HCV and HBV/HCV patients, or age above/below 40 years. Mean values (intra-individual variability) in plasma concentrations (mg/L) found in 3 of 31 patients who experienced virologic failure were 1.78 (42%), 1.52 (16%), and 1.68 (45%). The high interindividual variability and low maintained values of intrapatient variability in plasma concentrations support therapeutic drug monitoring, which could be based on measurements taken quarterly during the first year of therapeutics. In patients presenting high values of intra-individual variability (eg, >40%) associated with low plasma concentrations (eg, <2 mg/L), more frequent measurements over longer periods (more than 1 yr) of controlled concentrations might be recommended, but this requires further investigation.

Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children

“…After accounting for the effects of covariates on CL/F, the remaining interindividual and interoccasion variabilities in the EFV CL/F were still high (45.7 and 30.0%, respectively). Similarly high variability has been estimated in other studies, as well (4,5,54,55), and could be attributed to polymorphisms in metabolizing enzymes and to the unique circumstances that hinder adherence in HIV-infected children (30). About 20-to 250-fold interindividual variability is believed to exist in CYP2B6 expression at the levels of mRNA, protein, and catalytic activity (54).…”

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

“…This finding suggests that autoinduction exposes a few individuals to a risk of virological failure among populations previously known for high plasma concentrations and adverse effects of efavirenz. Quarterly therapeutic drug monitoring of patients on efavirenz, as suggested by Pereira et al [5], could play an important role in identifying such individuals and patients with nonadherence secondary to toxicity, especially in the African population where CYP2B6 polymorphism confers a risk of toxicity.…”

“…A plasma therapeutic range of 1-4mg/mL has been established for the nonnucleoside reverse transcriptase inhibitor efavirenz [1,2], and great variation in the pharmacokinetics of the drug exists within and between patients, causing variation in drug concentrations [3][4][5][6]. Factors reported to be associated with interpatient variability in efavirenz concentration include gender, ethnicity and genetic polymorphisms [3,4,7,8,36], while autoinduction and adherence [8,9] [3,4,7], while Black patients have been reported to exhibit lower rates of clearance of the drug and hence higher plasma concentrations [10].…”

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

“…Thus, when EFV is administered at a fixed dosage of 600 mg once daily, some patients suffer from central nervous system toxicity (trough steady-state plasma concentration [C ss min] Ͼ 4 g/ml) (6,29,34,42) or fail to achieve durable viral load suppression (C ss min Ͻ 1 g/ml) (4,18,19,22,34,37,43). These differential patient responses can, at least in part, be attributed to high interpatient variability in the disposition kinetics of EFV (41).…”