Background:  TMC125, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against both wild type HIV and viruses resistant to currently approved NNRTI, is likely to be used in addition to ritonavir (RTV)-boosted proteasae inhibitors (PI), including dual PI combinations. The objective of this trial was to evaluate the effect of TMC125 on PI concentrations in a dual boosted regimen.

Methods:  An open-label trial was conducted among HIV⁺ adults with previously documented NNRTI resistance and viral load <50 copies/mL for >8 weeks on a stable regimen comprising lopinavir (LPV)/RTV, saquinavir (SQV), and >2 NRTI. TMC125 800 mg twice daily was added to the ongoing regimen for 2 weeks starting on day 1. Safety was assessed during the entire trial period. Pharmacokinetic assessments were performed at 12-hour intervals on days –1 and 14, and pre-dose trough levels on day 7. Plasma concentrations of PI and TMC125 were determined by validated LC-MS/MS methods. Pharmacokinetic parameters for LPV, SQV, and RTV were analyzed using a linear mixed effect model. Comparison of TMC125 pharmacokinetic results with historical controls is ongoing.

Results:  Of 15 subjects, 13 were male. Median baseline values were:  age 46 years, weight 65 kg, body mass index 22.5 kg/m², CD4 cell count 321/mm³. Doses in mg of LPV/RTV/SQV taken twice daily were 400/100/1000 (n = 6), 400/100/800 (n = 5), 400/200/800 (n = 1), and 533/133/800 (n = 3). Concomitant ART included lamivudine (3TC) in all 15, plus a second NRTI, mainly abacavir (n = 6). All 15 patients completed the study and 9 (60%) reported >1 adverse event, mainly grade 1. No drug-related rashes or cardiac effects were seen. TMC125 reached steady state by day 7. After combined analysis of subjects receiving LPV/RTV/SQV 400/100/800 to 1000 (n = 11), C_min, C_max, and AUC_12h treatment ratios (day 14 / day –1) for LPV were 76%, 84%, and 82%; for RTV were 88%, 89%, and 87%; and for SQV were 87%, 85%, and 87%. Changes in LPV C_max and AUC_12h, but not C_min, were statistically significant (p = 0.03, 0.04, and 0.18, respectively), while changes in RTV and SQV pharmacokinetic parameters were not significant (p >0.3). Viral load remained <50 copies/mL throughout the study period.

Conclusions:  TMC125 800 mg twice daily was safe and well tolerated when given to HIV⁺ adults receiving stable regimens including LPV/RTV, SQV, and NRTI. LPV C_max and AUC_12h were statistically significantly lower, but LPV C_min and pharmacokinetic parameters for RTV and SQV did not change significantly after 2 weeks additional TMC125. The observed changes in plasma PI levels were of small magnitude (11 to 24%) and unlikely to be clinically significant.