Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398

Abstract

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Figures

FIG. 1.

Goodness-of-fit plots of the final PK model for EFV. Left panels, observed (OBS) concentrations (C) versus PRED and IPRED; heavy dashed lines, smoothing of concentrations versus PRED and IPRED. Right panels, population residuals (RES) and weighted individual residuals (IWRES) versus PRED and IPRED; heavy dashed lines, smoothing of RES (IWRES) versus PRED (IPRED). The fine dashed lines indicate lines of identity in the left panels and the ordinate value of 0 in the right panels.

FIG. 2.

MAP Bayes estimates of individual CL/F values obtained from the baseline PK model versus the covariate race (white non-Hispanic versus African American and Hispanic). Boxes, interquartile ranges (third quartile to first quartile); whiskers, 1.5 times the interquartile ranges; white horizontal lines, medians (50th percentile).

FIG. 3.

Probability of virological failure by 1 year versus scaled individual EFV CL/F among patients in AACTG study 398 with EFV PK data. (A) Patients previously exposed to NNRTIs; (B) patients not previously exposed to NNRTIs. CL/F is expressed as the percentage of the population average CL/F. Points are individual datum points: virological failure was given a value of 1, and virological nonfailure was given a value of 0. Data for only two individuals were censored before 300 days (plotted as nonfailures). The shaded areas in both plots delimit pointwise 90% confidence intervals obtained by bootstrapping (10) the data (500 replications). The solid central line in each plot is the mean of the bootstrapped smoothed data.