Intra-individual variability in efavirenz plasma concentrations supports therapeutic drug monitoring based on quarterly sampling in the first year of therapy.
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.
Pereira
Sofia A
SA
Department of Pharmacology, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal.
Branco
Teresa
T
Caixas
Umbelina
U
Côrte-Real
Rita M
RM
Germano
Isabel
I
Lampreia
Fátima
F
Monteiro
Emília C
EC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz