Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients

The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with hu man immunodeficiency virus randomized to receive either a double combinatio n of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a sub study of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured dur ing 44 of a total 48 weeks of study treatment, and a set of potential covar iates was available far nonlinear mixed-effect modeling analysis. A one-com partment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respect ively. Gender was the only covariate which significantly correlated with th e CL of NVP. ZDV and ddI data were described by a two-compartment model wit h zero-order input and first-order elimination. Individual mean oral CL, V- SS, (volume of distribution at steady state), and V of ZDV were 1.84 liters /h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age a s correlates of CL and body weight as a correlate of V-SS. The average indi vidual oral CL, V-SS, and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of bot h CL and V-SS. The relative bioavailability (F) of ZDV and ddI in the tripl e combination compared to that in the double combination was also evaluated . No significant effects of the combination regimens on the F of ddI were d etected (F-TRIPLE = 1.05 and F-DOUBLE = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was assoc iated with both ZDV and ddI pharmacokinetics. Individual cumulative area un der the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individu al data and the final-model estimates of structural and statistical paramet ers.