Limited sampling strategies for the estimation of the systemic exposure tothe HIV-1 nonnucleoside reverse transcriptase inhibitor nevirapine

The objective of this study was to develop and validate a limited sampling strategy (LSS) that allows accurate and precise estimation of the area unde r the plasma concentration versus time curve (AUC) of nevirapine, when used in the licensed dosage of 200 mg twice daily. Because nevirapine has a lon g plasma elimination half-life and the plasma concentration shows little va riation within the 12-hour dosing interval, the authors also wanted to expl ore whether a time frame exists for which a single-sample LSS can be applie d. Twenty HIV-1-infected individuals receiving steady-state treatment with nevirapine (200 mg twice daily) were enrolled. For the development of the L SS, 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 wer e obtained before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h ours after ingestion. The relationship between the nevirapine concentration at each of the designated time points and the AUC,2,, was evaluated by uni variate and multivariate linear regression analysis. At each of the samplin g times, a strong correlation was observed between the nevirapine concentra tion and the corresponding AUC(12h) (r > 0.97). This allows for a single-sa mple LSS, using any time point during the dosing interval. When a single: e quation is preferred, the concentration of nevirapine in a random sample dr awn 2 to 4 hours after ingestion of nevirapine (C2-4h; in mug/mL) can be us ed for accurate estimation of the AUC(12h) (in h(.)mug/mL) by using the equ ation AUC(12h) (h(.)mug/mL) = 11.699 (h) x C2-4h (mug/mL) - 4.381 (h(.)mug/ mL). Validation of this equation resulted in a predicted AUC(12h) that was nonbiased and very precise. These data show that the nevirapine concentrati on at each time point during the dosing interval can be used for accurate e stimation of the AUC(12h). Even more practical, a sample obtained at any ti me between 2 and 4 hours after ingestion of nevirapine can be used. The aut hors 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 d osage of 200 mg twice daily.