Kappelhoff and colleagues presented pharmacokinetic data from the 2NN study assessing the blood levels of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP, Viramune) and efavirenz (EFV, Sustiva, Stocrin). The researchers also investigated whether there were any patient characteristics that might have affected these blood levels.

The 2NN study was a multinational trial that compared first-line therapy with nevirapine, efavirenz or both combined with lamivudine (3TC, Epivir) and stavudine (d4T, Zerit). The results of the clinical trial were recently published in The Lancet.¹

In the study, treatment-naive patients with a viral load higher than 5,000 copies/mL were randomized into 4 arms: nevirapine 400 mg once daily; efavirenz 600 mg once daily; nevirapine 400 mg plus efavirenz 800 mg once daily; and nevirapine 200 mg twice daily. Each arm was combined with lamivudine and stavudine for 48 weeks.

Plasma samples were collected at day 3 and again at weeks 1, 2, 4, 24 and 48. Nevirapine and efavirenz levels were determined by high-performance liquid chromatography.

A total of 1,077 patients provided 3,024 and 1,694 samples for nevirapine and efavirenz blood levels, respectively. There were 2 or 3 times as many patients in the single-NNRTI arms compared to the dual-NNRTI arm of the study. In terms of patient characteristics, all arms were pretty much evenly matched: two-thirds of the patients were male, average age was 35 years, 5% were coinfected with hepatitis B, 9% were coinfected with hepatitis C and 25% came from western countries.

Kappelhoff presented data to show how the plasma levels that were generated were then used to generate a pharmacokinetic model to explain the relationship between absorption and elimination of nevirapine and efavirenz.

Significant findings demonstrated that nevirapine clearance (and therefore inter-individual variability) was significantly affected by female gender, hepatitis B virus infection and geographic location, whereas efavirenz clearance was only significantly affected by concomitant nevirapine administration or geographic location -- not by gender or hepatitis virus infection. Clearance of both drugs was similar throughout the study.

This study was presented to demonstrate validation of a pharmacokinetic model for these two NNRTIs using samples collected in the 2NN study. Correlation between NNRTI levels, patient demographic variables studied and treatment response was not presented in this study. Thus, although important differences were noted in the drug levels and clearance of these two NNRTIs, it is difficult to determine the clinical significance of these findings. It is also difficult to tell whether knowing that some demographic information will affect these blood levels, and measuring NNRTI blood levels in clinical practice would affect treatment outcome in any way.

Footnote

1. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. April 17, 2004;363(9417):1253-1263.