Development of the full model.

The full covariate model was developed by incorporating the effect of all prespecified covariate-parameter relationships, which were determined by clinical judgment and mechanistic plausibility. The covariate-parameter relationships assessed were as follows: the effects of age, weight, gender, race, prior antiretroviral therapy (PART; indicator of study PACTG1021), and concomitant protease inhibitor (PINT; nelfinavir or indinavir, indicator of study PACTG382) on CL; the effect of body weight on V_C; and the effects of age, weight, and formulation on K_a. For continuous covariates (age and body weight), the relationship between the typical value of a parameter (P_TV) and a continuous covariate (R) at each clinic visit was tested using the equation P_TV = P1(R/R_ref)^P2, where P1 and P2 are fixed-effect parameters and R_ref is a reference value of the covariate. Both age and weight were incorporated as time-varying covariates. For categorical covariates (sex, race, prior antiretroviral therapy, concomitant protease inhibitor, and formulation), the relationship between the typical value of a parameter P_TV and a categorical covariate (R) was tested using the equation P_TV = P1 (1 + R · P2), where P1 and P2 are fixed-effect parameters. Covariates were included simultaneously using a full-model approach, followed by the procedure for Wald's approximation method (WAM) (16).