Pett Sarah L, McCarthy Michael C, Cooper David A, MacRae Karen, Tendolkar Amol, Norris Richard, Strizki Julie M, Williams Kenneth M, Emery Sean
HIV, Immunology and Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia.
Antivir Ther. 2009;14(1):111-5.
SCH532706 is a novel small molecule chemokine receptor-5 (CCRS) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC90] 0.15-7.0 nM) against diverse HIV type-1 (HIV-1) isolates.
A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients.
The study enrolled 12 males with CD4+ T-cell count >100 cells/microl. Median (range) CD4+ T-cell count was 327 cells/microl (117-1008), HIV-1-RNA was 4.6 log10 copies/ml (3.8-5.5) and patients had phenotypically confirmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1-RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log10 copies/ml (-1.6 - -1.0) and -1.62 log10 copies/ml (-2.0 - -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (+/-SD) effective half-life and mean (+/-SD) trough concentration were 1.4 h (1.0-4.0), 39.4 h (+/-14.5) and 178 ng/ml (+/-34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported > or =1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug.
Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC90 (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.
SCH532706是一种新型小分子趋化因子受体-5（CCR5）拮抗剂，对多种1型人类免疫缺陷病毒（HIV-1）分离株具有较高的体外活性（平均90%抑制浓度[IC90]为0.15 - 7.0 nM）。
开展一项单臂研究，以检测与利托那韦（RTV）联合使用10天的SCH532706的安全性、抗病毒活性及药代动力学（PK）。该试验纳入了既往接受过治疗（停药超过3个月）或未接受过治疗的HIV-1感染患者。
该研究纳入了12名CD4 + T细胞计数>100个/微升的男性。CD4 + T细胞计数中位数（范围）为327个/微升（117 - 1008），HIV-1-RNA为4.6 log10拷贝/毫升（3.8 - 5.5），且患者仅具有经表型确认的R5嗜性HIV-1。第10天和第15天（停用SCH532706 4天后）血浆HIV-1-RNA相对于基线的平均（95%置信区间）变化分别为-1.31 log10拷贝/毫升（-1.6 - -1.0）和-1.62 log10拷贝/毫升（-2.0 - -1.3）。第10天达到最大血浆浓度的中位（范围）时间、平均（±标准差）有效半衰期和平均（±标准差）谷浓度分别为1.4小时（1.0 - 4.0）、39.4小时（±14.5）和178纳克/毫升（±34）。所有病毒分离株在研究前、研究期间及研究结束时均保持R5嗜性。没有可报告为不良事件的实验室或QTc间期变化。总共11名患者报告了≥1次治疗中出现的不良事件，最常见的是胃肠道不适。1例严重不良事件，心包炎（2级），在给药13天后发生。它被认为可能与研究药物有关。
总体而言，SCH532706与RTV联合用药在10天给药期间是安全的，一般耐受性良好且对HIV-1有活性。在此情况下，SCH532706的谷浓度超过平均体外IC90（1.1纳克/毫升）30倍以上（校正80%血浆蛋白结合后），并为观察到的疗效提供了药代动力学依据。
