Background:  SCH532706 is a CCR5 antagonist with high in vitro potency (IC₉₀ <10 nM) against 30 different HIV-1 isolates. This protocol examined the safety, antiretroviral activity, and pharmacokinetic profile of ritonavir (RTV) -boosted SCH532706 in ART-naïve or ART-experienced patients not currently treated.

Methods:  This study was a fixed-sequence, open-label, non-randomized, single-center study of 10-day monotherapy with SCH532706 (60 mg twice daily) and RTV (100 mg once a day) in ART-naive or -experienced HIV-infected patients with R5 virus ready to start/resume combination ART (cART). Intensive pharmacokinetics monitoring was performed on days 1 and 10; cART was commenced following a 15-day washout.

Results:  We enrolled 12 HIV-infected males (4 ART-naive, 8 ART-experienced). Median age was 36 years (range 30 to 52); mean CD4⁺ T cell count and plasma HIV RNA log₁₀ copies/mL were 385 cells/µL (26%), and 4.56, respectively. Mean changes from baseline plasma HIV RNA at days 10 and 15 (4 days after study drug ceased) were –1.31 (95%CI –1.6 to –1.0) and –1.62 log₁₀ copies/mL (95%CI –2.0 to –1.3). Day 10 mean C_max, median T_max, mean AUC (Tau) and mean effective t_1/2 for SCH532706 were 295(SD 45) ng/mL, 1.4 (range 1.0 to 4.0) hours, 2780 (SD 444) ng.hr/mL and 39.4(SD 14.5) hours, respectively. Mean day 10 trough plasma concentration was 186 (SD 35) ng/mL, a level >30-fold higher (after correction for plasma protein binding of 80%) than the in vitro IC₉₀ value of 1.1 ng/mL. All virus isolates remained R5 tropic throughout the study period. There were no abnormal clinical safety laboratory tests reported as adverse events or clinically significant changes in electrocardiographic parameters. Of the total, 11 subjects reported >1 treatment-emergent adverse events, most commonly gastrointestinal upset; 72% of adverse events were mild (grade 1); 66% were considered unlikely to be related to SCH532706; 1 serious adverse event, moderate pericarditis, occurred 13 days post last dose of RTV-SCH532706 and was considered possibly related to study drug; this resolved spontaneously with no sequelae after 4 days.

Conclusions:  RTV-boosted SCH532706 (60 mg twice daily) was safe, well tolerated, and biologically active against HIV-1 with maximum decline in plasma HIV RNA of –1.62 log₁₀ copies/mL at day 15. The high trough level concentrations of SCH532706 in comparison to its in vitro IC₉₀ value, provide pharmacokinetic rationale for the observed efficacy.