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Relationships between Efavirenz Pharmacokinetics, Side Effects, Drug Discontinuation, Virologic Response, and Race: Results from ACTG A5095/A5097s
H Ribaudo*1, D Clifford2, R Gulick3, C Shikuma4, K Klingman5, S Snyder6, and E Acosta7
1Harvard Sch. of Publ. Hlth., Boston, MA, USA; 2Washington Univ., St. Louis, MO, USA; 3Cornell Univ., New York, NY, USA; 4Univ. of Hawaii, Honolulu, USA; 5DAIDS, NIAID, NIH, DHHS, Bethesda, MD, USA; 6Social and Sci. Systems, Inc., Silver Spring, MD, USA; and 7Univ. of Alabama at Birmingham, USA
Background: Central nervous system (CNS) side effects occur commonly with efavirenz (EFV).
We assessed the relationship of EFV pharmacokinetics, side effects, drug
discontinuation, virologic response, and patient characteristics.
Methods: ACTG A5095 is a double-blind clinical trial of
initial antiretroviral therapy, including EFV-containing regimens, in
treatment-naïve subjects; A5097s was a substudy that evaluated CNS side effects over the first 24 weeks of
treatment. Plasma samples collected at weeks 1, 4, 12, and 24 in subjects
taking EFV in ACTG A5095 and co-enrolled in A5097s were tested for EFV drug
levels. Empirical Bayes estimates of drug clearance and volume of distribution
were obtained using a first-order single-compartment recursive population pharmacokinetics
model. Associations between clearance and volume of distribution and weight,
sex, and race of the study subjects were examined within this model and
verified with non-parametric tests of the empirical Bayes estimates. The
associations between estimated clearance, Cmax and Cmin
(derived from the empirical Bayes estimates) and the distribution of time to
discontinuation of EFV, first CNS
toxicity and first HIV-1 RNA viral load of <200 copies)/mL were examined
using Cox proportional hazards models with empirical Bayes estimates divided
according to tertiles.
Results: Of the 202
eligible subjects, samples from 190 subjects were available for analyses: 36 (19%) women and 154 (81%) men. Median
weight was 75 kg (range: 46 to 186 kg).
Race distribution was 100 (53%) white, 61 (32%) black, and 29 (15%) Hispanic. Race
was strongly associated with clearance: there
was a 32% increase (95% CI = 15%, 51%; p <0.001;
Wilcoxon test) in clearance among white non-Hispanic subjects compared with
black and Hispanic subjects. Both clearance and volume of distribution were
associated with weight (p <0.001).
There was no apparent association with gender (p >0.26). During study follow-up, 31 subjects (16%) discontinued
EFV, primarily because of: CNS symptoms (n
= 5), rash (n = 5), other toxicity (n = 4), subject/clinician decision (n = 6), and non-compliance (n = 6). There was some evidence of an
increasing rate of EFV discontinuation with decreasing clearance (p = 0.052) and increasing Cmax
(p = 0.048). There was no apparent
association between EFV pharmacokinetics and rates of first CNS toxicity or viral load of <200 copies/mL
(for clearance, p = 0.99, p = 0.46, respectively).
Conclusions: EFV clearance is strongly associated with
race. Increasing EFV drug levels was associated with an increased rate of EFV
discontinuation. There was no association with EFV pharmacokinetics and the
incidence of CNS toxicities or viral
load response.
Keywords: efavirenz; pharmacokinetics/pharmacodynamics; racial differences
