Background:  TMC125 is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against both wild type and NNRTI-resistant HIV. Study TMC125-C223 prospectively randomized 199 HIV-infected patients with NNRTI resistance and ≥3 primary protease inhibitor (PI) mutations at baseline to TMC125 (400 or 800 mg twice daily) with an investigator selected optimized background or standard-of-care control regimen. This analysis investigated demographic effects on TMC125 pharmacokinetic and pharmacokinetic/pharmacodynamic relationships from this trial.

Methods:  A population pharmacokinetic model for TMC125 was developed with Bayesian feedback for AUC_12h and C_0h from sparse sampling collected over 48 weeks. Virologic response was defined as change in viral load from baseline, ≥1 log drop in viral load or % <50 copies/mL. ANCOVA and logistic regression were used to analyze pharmacokinetic/ pharmacodynamic relationships.

Results:  Median baseline viral load was 4.7 log₁₀ copies/mL. At 48 weeks, the mean viral load reduction (intent to treat NC = F) was –0.88, –1.01 and –0.14 log₁₀ copies/mL for the 400-mg, 800-mg, and control arms, respectively; the difference for both TMC125 doses versus control was significant (p <0.05). Pharmacokinetics from 150 patients receiving TMC125 were available for analysis (75 patients on each dose). The estimated population pharmacokinetic mean (SD) AUC_12h (ng•h/mL) and C_0h (ng/mL) for TMC125 400 mg twice daily was 3952.3 (3193.87) and 240.2 (204.38), respectively and for TMC125 800 mg twice daily was 6930.6 (6177.73) and 416.0 (370.48), respectively. Multivariate analysis including sex, age, weight, race, hepatitis status, dose, and use of a PI (mostly boosted lopinavir) or tenofovir (TDF) in the OB showed that 400 mg twice daily, use of a PI or TDF were each independently associated with lower TMC125 pharmacokinetic (p <0.05); the combined use of a PI and TDF did not further decrease TMC125 pharmacokinetic. Virological response at weeks 24 and 48 were significantly associated with TMC125 pharmacokinetic when evaluating both dose groups combined but not the 800-mg dose group alone. No apparent relationships were seen between TMC125 pharmacokinetic and laboratory changes or adverse events.

Conclusions:  Baseline characteristics do not significantly alter TMC125 pharmacokinetic, while use of a PI or TDF was associated with lower TMC125 pharmacokinetic. No relationships were observed between TMC125 pharmacokinetic and virological response in the 800-mg dose group, thus dose adjustment for PI and TDF is not necessary; pharmacokinetic/pharmacodynamic relationships were also absent for safety. Phase III studies of TMC125 are currently ongoing with a new formulation that when dosed at 200 mg twice daily provides comparable exposure to 800 mg twice daily but with improved bioavailability and reduced pill count.