Pharmacokinetic Assessment of Nevirapine and Metabolites in Human Immunodeficiency Virus Type 1-Infected Patients with Hepatic Fibrosis

Abstract

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for >6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients

“…In agreement with others, no relationship between nevirapine clearance and weight was evidenced (11,22). No modification in nevirapine pharmacokinetics was seen in patients with liver disease (8,11), and no relationship between ALAT and nevirapine concentrations was found in the present study.…”

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

“…Our plasma samples were not hydrolyzed; therefore, the plasma ratio of hydroxynevirapine to its glucuronide is not available in our study. A comparison of steadystate trough plasma concentrations in our patients with concentrations measured in HIV-infected patients with mild liver fibrosis (13) showed that nonconjugated 2-hydroxynevirapine and 3-hydroxynevirapine concentrations are well below those of the glucuronides, which remained lower than those of nevirapine, roughly 2 ng/ml versus 177 ng/ml and 12 ng/ml versus 759 ng/ml, respectively. In contrast, 8-hydroxynevirapine and 12-hydroxynevirapine concentrations are closed whether plasma was hydrolyzed or not (29 versus 31 ng/ml and 504 versus 142 ng/ml, respectively), indicating that glucuronide concentrations of these metabolites in plasma are low.…”

“…These metabolites are eliminated in the urine as conjugates, mainly glucuronides (14). Relatively little is known regarding nevirapine biotransformation and metabolite disposition following a single dose and at steady state, in part due to the lack of a direct and sensitive assay (13,15).…”

“…In vitro microsome data suggest that CYP3A is involved in 2-hydroxynevirapine formation and CYP2B6 is involved in 3-hydroxynevirapine formation (12). Several CYPs are involved in the other pathways (12,13). These metabolites are eliminated in the urine as conjugates, mainly glucuronides (14).…”

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

“…Strong correlations were observed between 2-OH NVP and nevirapine concentrations while 3-OH NVP and nevirapine demonstrated weak correlations. In a study to assess the pharmacokinetics of nevirapine and metabolites in patients with hepatic fibrosis, the metabolite profiles were comparable across the stages of the disease (11). Risk of virological failure increased 5-fold when nevirapine concentrations were below 3 mg/L and dose adjustment has been suggested if the nevirapine Cmin is lower than 3 mg/L (12,13).…”