Tashima Karen, Crofoot Gordon, Tomaka Frank L, Kakuda Thomas N, Brochot Anne, Vanveggel Simon, Opsomer Magda, Garner William, Margot Nicolas, Custodio Joseph M, Fordyce Marshall W, Szwarcberg Javier
The Miriam Hospital, Providence, RI, USA.
Gordon Crofoot Research, Houston, TX, USA.
J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19772. doi: 10.7448/IAS.17.4.19772. eCollection 2014.
COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug-drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers.
This 48-week, phase IIIb, open-label, single-arm, US multicentre study (NCT01440569) included HIV-infected treatment-nave and experienced adults with no DRV RAMs, viral load (VL) ≥1000 c/mL, eGFR ≥80 mL/min and genotypic sensitivity to investigator-selected N[t]RTIs. Patients received DRV/COBI 800/150 mg qd (as single agents) plus two fully active N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 AEs through Week 24. We report 48-week safety, efficacy and PK/PD results in treatment-nave patients.
Of 313 ITT patients, 295 were treatment-nave (94%). In the treatment-nave cohort, 90% were male, 60% white and 294 (99.7%) received a TDF-containing regimen. Median baseline (BL) VL was 4.8 log10 c/mL and CD4(+) 370 cells/mm(3). Treatment-emergent grade 3 or 4 AEs regardless of causality were reported in 21 (7%) patients. AEs regardless of causality (any grade; ≥10% of patients) were: diarrhoea (27%), nausea (23%), URTI (15%) and headache (12%). Sixteen (5%) patients had AEs leading to study drug discontinuation, most frequently rash (three patients), hypersensitivity and nausea (two patients each). Consistent with the known inhibition of tubular creatinine secretion by COBI, there was a mean increase from BL in serum creatinine by week 2 (0.09 mg/dL), remaining stable through week 48 (mean 0.10 mg/dL increase from BL). At week 48, 83% of patients achieved VL<50 c/mL; FDA Snapshot); median increase in CD4(+) was 169 cells/mm(3). Eight patients met the criteria for resistance testing. M184V was detected in one pt receiving FTC. New primary RAMs were not detected in the other seven patients. The mean population PK-derived DRV AUC24h was 100,620 ng.h/mL and C0h 2,105 ng/mL (n=281). There were no clinically relevant relationships between DRV exposure and virologic response, AEs or laboratory parameters.
The DRV PK of DRV/COBI was consistent with historical data for DRV/RTV. DRV/COBI 800/150 mg qd plus two N(t)RTIs had an 83% response and was well tolerated through Week 48. These results are similar to published data for DRV/RTV 800/100 mg qd, and support the use of DRV/COBI 800/150 mg qd in treatment-nave patients.
COBI是一种无抗逆转录病毒活性的药代动力学增强剂，是一种比利托那韦（RTV）更具选择性的细胞色素P450（CYP）3A抑制剂，不会诱导CYP同工酶，因此药物相互作用的可能性较小。在健康志愿者中，COBI提高达芦那韦（DRV）药代动力学的效果与RTV一样有效。
这项为期48周、IIIb期、开放标签、单臂、美国多中心研究（NCT01440569）纳入了未接受过DRV治疗且无DRV相关不良事件（RAMs）、病毒载量（VL）≥1000拷贝/mL、估算肾小球滤过率（eGFR）≥80 mL/分钟且对研究者选择的核苷类逆转录酶抑制剂（N[t]RTIs）基因型敏感的HIV感染成人患者。患者接受DRV/COBI 800/150 mg每日一次（作为单一药物）加两种全效N[t]RTIs。主要终点是至第24周出现的任何3级或4级治疗中出现的不良事件（AE）。我们报告了未接受过治疗患者的48周安全性、疗效及药代动力学/药效学（PK/PD）结果。
在313例意向性分析（ITT）患者中，295例为未接受过治疗的患者（94%）。在未接受过治疗的队列中，90%为男性，60%为白人，294例（99.7%）接受了含替诺福韦（TDF）的治疗方案。基线（BL）VL中位数为4.8 log10拷贝/mL，CD4(+)细胞计数为370个/mm³。21例（7%）患者报告了无论因果关系的治疗中出现的3级或4级AE。无论因果关系的AE（任何级别；≥10%的患者）为：腹泻（27%）、恶心（23%）、上呼吸道感染（URTI，15%）和头痛（12%）。16例（5%）患者出现导致研究药物停用的AE，最常见的是皮疹（3例患者）、超敏反应和恶心（各2例患者）。与COBI对肾小管肌酐分泌的已知抑制作用一致，血清肌酐从基线至第2周平均升高（0.09 mg/dL），至第48周保持稳定（较基线平均升高0.10 mg/dL）。在第48周，83%的患者实现了VL<50拷贝/mL；FDA快照）；CD4(+)细胞计数中位数增加为169个/mm³。8例患者符合耐药性检测标准。在1例接受恩曲他滨（FTC）的患者中检测到M184V。在其他7例患者中未检测到新的主要RAMs。基于群体药代动力学的DRV 24小时曲线下面积（AUC24h）平均值为100,620 ng·h/mL，0小时浓度（C0h）为2,105 ng/mL（n = 281）。DRV暴露与病毒学反应、AE或实验室参数之间无临床相关关系。
DRV/COBI的DRV药代动力学与DRV/RTV的历史数据一致。DRV/COBI 800/150 mg每日一次加两种N(t)RTIs的病毒学应答率为83%，且至第48周耐受性良好。这些结果与已发表的DRV/RTV 800/100 mg每日一次的数据相似，并支持在未接受过治疗的患者中使用DRV/COBI 800/150 mg每日一次。
