Background:  TMC114 is an HIV protease inhibitor (PI) that is potent against wild type and PI-resistant HIV. TMC114 is administered with low-dose ritonavir (TMC114/RTV). POWER 1 (TMC114-C213) and POWER 2 (TMC114-C202) are ongoing randomized, controlled, phase IIb studies to evaluate dose-response after 24 weeks in 3-class-experienced patients with ³1 primary PI mutation. We compared with control PI regimens, 4 TMC114/RTV doses (400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily, and 600/100 mg twice daily). An optimized background regimen) consisting of nucleoside reverse transcriptase inhibitors ± enfuvirtide (EFV) was used in each treatment arm.

Methods:  Blood sampling was performed in patients randomized to the TMC114/RTV groups to determine TMC114 PK parameters area under the curve and trough concentration in 468 patients. At week 24, pharmacokinetic/pharmacodynamic relationships were assessed for TMC114 using analysis of covariance models. Efficacy PD measures tested in the model included change in viral load from baseline and proportion of patients with ³1.0 log₁₀ decrease in viral load. Inhibitory quotients (IQ), the ratio between steady state TMC114 trough concentration and baseline TMC114 EC₅₀ were also related to the efficacy PD measures. Relationships between TMC114 pharmacokinetic and safety parameters were investigated using descriptive methods.

Results:  The relationship between TMC114 pharmacokinetic parameters and efficacy (virologic and response parameters), though statistically significant was strongly influenced by baseline TMC114 fold change, baseline viral load and use of sensitive drugs in the optimized background regimen. The IQ was the strongest predictor of virologic response, with the relationship primarily driven by baseline TMC114 fold change. The relationship between TMC114 pharmacokinetic parameters and efficacy parameters was observed mainly in patients whose baseline TMC114 fold change was between 4 and ≤40. There was no clear relationship between TMC114 pharmacokinetic/ parameters and efficacy parameters in patients with TMC114 fold change values >40, nor in patients with TMC114 fold change values £4. IQ values of TMC114 were generally high (mean values >200) and increased with dose, with the highest IQ values observed in the TMC114/RTV 600/100 mg twice daily group. There was no apparent relationship between TMC114 pharmacokinetic parameters and safety measures.

Conclusions:  Pharmacokinetic/pharmacodynamic relationships for TMC114 provide evidence to support the recommendation of the 600/100 mg twice daily dosing regimen in treatment-experienced HIV-1-infected patients.