Sex differences in nevirapine disposition in HIV-infected patients

To evaluate the role of sex in nevirapine pharmacokinetics, we analysed the pharmacokinetic profile of nevirapine in 11 male and 11 female HIV-positive patients chronically treated with nevirapine 400 mg once a day. Statistically significant inter-group differences in the plasma concentration and fluctuations between that and the concentration just before the next dose, at steady-state, were observed. Variations in lean body mass and composition affecting nevirapine distribution might account for inter-sex discrepancies in nevirapine plasma levels. Sex differences reported in the plasma levels for some antiretroviral drugs may be involved in the higher incidence of adverse reactions observed in women compared with men [1,2]. In particular, an overall higher frequency of nevirapine-induced rash has been reported among women. The biological bases for this difference are unknown. The increased incidence of rash in patients started on nevirapine therapy without dosage escalation suggests a possible dose–response relationship [3]. To evaluate the role of sex in nevirapine pharmacokinetics, we analysed the pharmacokinetic profile of nevirapine in a cohort of male and female HIV-positive patients. Twenty-two HIV-infected patients (11 men and 11 women) chronically treated (> 4 weeks) with nevirapine 400 mg once a day plus two nucleoside analogues (zidovudine plus lamivudine, stavudine plus didanosine or stavudine plus lamivudine) were enrolled. On pharmacokinetic analysis, liver and kidney function tests were performed and CD4 cell counts and plasma HIV-RNA levels were assayed (Monitor Amplicor, Roche Diagnostic Systems, Branchburg, NJ, USA). Patients were eligible for the study if alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase levels were up to three times the upper normal limit, and total bilirubin and creatinine levels were up to 1.5 times the upper normal limit. Exclusion criteria were: pregnancy; the use of drugs known to induce or inhibit hepatic enzymes; active intravenous drug use or alcohol abuse; and oral contraceptives in women. Informed consent was obtained from all study participants, and institutional human experimentation guidelines were followed. Nevirapine (400 mg a day) was taken after overnight fasting. Patients underwent serial blood samplings at 0, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after nevirapine ingestion. Nevirapine plasma concentrations were quantified using a modified version of a validated, sensitive, high-pressure liquid chromatography assay [4]. The assay, linear from 50 to 10 000 ng/ml, was validated for precision and accuracy. The inter and intra-assay coefficients of variation (CV%) of precision of the quality control samples were always less than 10% for all evaluated concentrations. The maximum nevirapine plasma concentration (Cmax), corresponding time (Tmax), concentration just before the next dose (Ctrough), and the difference between Cmax and Cmin (ΔC) during the dosing interval τ were determined by analysing the individual plasma concentration-time profiles for both groups of patients. The area under the plasma concentration-time curve from time 0 to 24 h (AUC0–24) was calculated using the trapezoidal method. Oral clearance (CL/F, with F as the fraction of the absorbed dose, assumed to be equal to 1) was calculated as dose/AUC. Inter-group differences between the pharmacokinetic parameters of nevirapine were evaluated using the analysis of variance. A P value of less than 0.05 was considered statistically significant. The two groups of patients were comparable for age, CD4 cell count and plasma HIV-RNA levels. In men compared with women the total body weight (TBW; 70.4 versus 54.3 kg, respectively) and lean body mass (LBM; 64.4 ± 6.2 versus 42.7 ± 9.6, respectively) were significantly higher (P < 0.005). No adverse events occurred during the study. The mean pharmacokinetic parameters of nevirapine at steady-state in the two groups of patients, at the dosage regimen of 400 mg a day, are shown in Table 1.Table 1: Mean (± SD) nevirapine pharmacokinetic parameters.The only slight increase (20%, P = 0.29) in AUC mean values observed in women is partly based on TBW differences between women and men. Correcting for the TBW differences, CL/F mean values overlapped in the two groups of patients, suggesting no differences in drug metabolism if any counterbalancing effect on drug absorption is excluded. We found no inter-group differences for Ctrough, but a statistically significant difference was seen for Cmax and ΔC, which were higher in women than in men. While normalizing data to the same dose/kg, the inter-group difference was no longer statistically significant, pooled data showed a correlation between ΔC and LBM (ΔC, μg/ml = 18.3e−0.045 * LBM,kg, r = 0.61). This suggests that differences in nevirapine distribution, attributable to variations in LBM and composition, might account for the inter-sex discrepancies in nevirapine plasma levels. Elevated drug concentrations may result in a higher risk of side-effects, as reported for the central nervous system in patients receiving efavirenz [5] or ritonavir [6]; thus, different pharmacokinetic values might be responsible for the inter-sex differences in side-effects. It has been demonstrated that women may be at a higher risk than men of cutaneous hypersensitivity reactions from nevirapine [7]. Rash pathogenesis remains uncertain as no relationship between rash and nevirapine plasma levels was found in one study [3], whereas a correlation was suggested in two other studies [8]. Administering the same drug dosage to women and men at the same frequency, without considering LBM differences, might predispose women to develop dose-related adverse reactions to nevirapine. From a pharmacokinetic viewpoint, twice daily dosing might be preferable in patients with very low LBM, to ensure lower peak and higher trough nevirapine plasma levels.