Limited Sampling Strategies for the Estimation of the Systemic Exposure to the HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor Nevirapine

Abstract

The objective of this study was to develop and validate a limited sampling strategy (LSS) that allows accurate and precise estimation of the area under the plasma concentration versus time curve (AUC) of nevirapine, when used in the licensed dosage of 200 mg twice daily. Because nevirapine has a long plasma elimination half-life and the plasma concentration shows little variation within the 12-hour dosing interval, the authors also wanted to explore whether a time frame exists for which a single-sample LSS can be applied. Twenty HIV-1-infected individuals receiving steady-state treatment with nevirapine (200 mg twice daily) were enrolled. For the development of the LSS, 10 patients were randomly selected from the study population (index set). The pharmacokinetic results from the other 10 patients (validation set) were used for prospective validation of the proposed LSS. Blood samples were obtained before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after ingestion. The relationship between the nevirapine concentration at each of the designated time points and the AUC 12h was evaluated by univariate and multivariate linear regression analysis. At each of the sampling times, a strong correlation was observed between the nevirapine concentration and the corresponding AUC 12h (r > 0.97). This allows for a single-sample LSS, using any time point during the dosing interval. When a single equation is preferred, the concentration of nevirapine in a random sample drawn 2 to 4 hours after ingestion of nevirapine (C 2-4h; in microg/mL) can be used for accurate estimation of the AUC 12h (in h x microg/mL) by using the equation AUC 12h (h x microg/mL) = 11.699 (h) x C 2-4h (microg/mL) - 4.381 (h x microg/mL). Validation of this equation resulted in a predicted AUC 12h that was nonbiased and very precise. These data show that the nevirapine concentration at each time point during the dosing interval can be used for accurate estimation of the AUC 12h. Even more practical, a sample obtained at any time between 2 and 4 hours after ingestion of nevirapine can be used. The authors therefore conclude that less intensive sampling (i.e., a single sample) can readily be used to assess the AUC 12h of nevirapine when used in a dosage of 200 mg twice daily.

Limited-Sampling Strategies for Anti-Infective Agents: Systematic Review

“…Six studies of limited-sampling strategies were considered to present evidence of the highest quality (level I), describing strategies for didanosine, 25 zidovudine, 26 nevirapine, 27 ciprofloxacin, 28 efavirenz, 29 and nelfinavir 30 ( Table 2). Each study used prospectively collected data and proper validation procedures.…”

“…All 6 studies randomized pharmacokinetic data into index and validation groups, and 5 of the studies clearly randomized the pharmacokinetic data into independent data sets. 25,[27][28][29][30] Each study illustrated the potential utility of limitedsampling strategies by requiring only 1 or 2 blood samples to predict AUC, with minimal bias and relatively good precision. The level I studies of didanosine and zidovudine also provided 1-sample limited-sampling strategies to predict a second pharmacokinetic parameter, maximum drug concentration (C max ).…”

“…27 In that study, all 14 sampling data points were used to determine a 1-sample (i.e., a random sample between 2 and 4 h after dosing) limitedsampling strategy that predicted the AUC with minimal bias and good precision. 27 This single "random" sample would be a convenient method for future research to determine if the AUC for nevirapine correlates with clinical outcome. A distinctive strength of the efavirenz study was that concomitant medications were accounted for in the randomization scheme.…”

“…23,24 Table 2 summarizes the characteristics of the included studies [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] according to their levels of evidence. The following information was extracted from each study: level of evidence, the antiinfective agent, the population for derivation of the limitedsampling strategy, the sampling times investigated, the suggested timed samples, the equation(s) for the limited-sampling strategy, r (the correlation coefficient) or r 2 , the percent bias for the validation group, the percent precision, and additional comments.…”

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

“…Additionally, pharmacokinetic measurements were obtained at 1 h (Ϯ15 min), 2 h (Ϯ30 min), and 4 h (Ϯ 30 min) after the morning nevirapine administration for a subset of patients (n ϭ 34). Limited sampling schemes have shown that the accuracy of the results by analysis of a single sample of nevirapine at steady state is within 14% of the true area under the plasma concentrationtime curve (AUC) because the drug has a half-life of Ͼ24 h and is administered twice daily (16). The pharmacokinetics of nevirapine and the five metabolites in all patients were characterized by noncompartmental methods with the pharmacokinetic and statistical software program WinNonlin (Pharsight Corp., Mountain View, CA).…”