Rational Dose Selection for a Nonnucleoside Reverse Transcriptase Inhibitor through Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation

Abstract

In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC ₉₀ ) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg). Monte Carlo simulation was performed, assuming a log-normal distribution for 1,000 simulated subjects for each dose, and was repeated three times. The trough concentrations were divided by 76 to account for protein binding and for the difference between EC ₅₀ and EC ₉₀ . We then determined the fraction of the simulated population whose free drug trough concentrations would exceed an EC ₉₀ over a broad range of values. The target attainment for all three doses exceeded 95% out to a starting EC ₅₀ of 10 nM. For 16 viral isolates, the EC ₅₀ range encountered for GW 420867X did not exceed 8 nM, implying that the three doses could not be differentiated by effect in a clinical trial in naive patients. This prediction was shown to be correct in a randomized, double-blind trial with 1 week of monotherapy with GW 420867X.