Background:  TMC125 is a next generation NNRTI with potent activity against both wild type and NNRTI-resistant HIV. DUET-1 and -2 are identically designed, ongoing phase III, double-blind, randomized trials of TMC125 vs placebo, both with a background regimen including darunavir/ritonavir (DRV/r) and other antiretrovirals in treatment-experienced patients. In the pooled intent-to-treat population at 24 weeks (n = 1203), TMC125 was consistently superior to placebo with respect to the following endpoints:  confirmed viral load <50 copies/mL (59 vs 41%), viral load <400 copies/mL (74 vs 53%), and mean viral load reduction (2.4 vs 1.7 log₁₀ copies/mL) (all p <0.0001). This analysis investigated demographic effects on TMC125 pharmacokinetics and pharmacokinetic/pharmacodynamic relationships from these trials.

Methods:  A population pharmacokinetic model for TMC125 phase III formulation was developed with Bayesian feedback for area under the plasma concentration-time curve (AUC) and pre-dose plasma concentration (C_0h) from sparse sampling collected over 24 weeks in the main study and from intensive pharmacokinetics in a substudy. ANCOVA, logistic regression and generalized additive modeling were used to analyze pharmacokinetic/pharmacodynamic relationships with efficacy endpoints and safety.

Results:  Of the 1203 patients enrolled, 599 were randomized to TMC125 and pharmacokinetic data from 574 were available. The estimated TMC125 population mean (SD) AUC and C_0h was 5501 (4544) ng·h/mL and 393 (378) ng/mL, respectively. Clearance (CL/F) was estimated to be 43.7 L/h and intersubject variability on CL/F was 60%; intrasubject variability on fraction absorbed was 40%. Covariate analysis including sex, age, weight, race, creatinine clearance, viral hepatitis status, and use of tenofovir (TDF) or enfuvirtide (ENF) in the background regimen showed that none of these factors significantly affected TMC125 pharmacokinetics. TMC125 AUC or C_0h was not associated with the primary endpoint of reaching <50 copies/mL at week 24. Other factors including baseline viral load and CD4, use of active agents, fold-change in EC₅₀ to DRV and TMC125, and adherence are more important determinants than pharmacokinetics. No apparent relationships were seen between TMC125 pharmacokinetics and laboratory changes or adverse events.

Conclusions:  TMC125 200mg twice daily demonstrated superior activity compared to placebo in treatment-experienced patients. Achieving <50 copies/mL in this setting was not influenced by TMC125 pharmacokinetics but rather the choice in background regimen and adherence to medication. Despite pharmacokinetic variability, no dose adjustments are needed for TMC125 based on covariate analysis and the lack of pharmacokinetic/pharmacodynamic relationships.