Ofotokun Ighovwerha, Acosta Edward P, Lennox Jeffrey L, Pan Yi, Easley Kirk A
Department of Medicine, Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, Georgia 30303, USA.
Pharmacotherapy. 2008 Jan;28(1):74-81. doi: 10.1592/phco.28.1.74.
To evaluate the pharmacokinetic compatibility of a ritonavir-boosted indinavir-fosamprenavir combination among patients with human immunodeficiency virus (HIV).
Single-center, nonrandomized, prospective, multiple-dose, two-phase pharmacokinetic study.
University research center.
Eight adult patients with HIV infection who had been receiving and tolerating indinavir 800 mg-ritonavir 100 mg twice/day for at least 2 weeks. Intervention. After 12-hour pharmacokinetic sampling was performed on all patients (period A), fosamprenavir (a prodrug of amprenavir) 700 mg twice/day was coadministered for 5 days, with a repeat 12-hour pharmacokinetic sampling performed on the fifth day (period B).
Pharmacokinetic parameters were determined for indinavir, ritonavir, and amprenavir: area under the concentration-time curve from time 0 to 12 hours after dosing (AUC(0-12)), maximum plasma concentration (C(max)), and 12-hour plasma concentration (C(12)). For each parameter, the geometric mean, as well as the geometric mean ratio (GMR) comparing period B with period A, were calculated. Indinavir C(max) was lowered by 20% (GMR 0.80, 95% confidence interval [CI] 0.67-0.96), AUC(0-12) was lowered by 6% (GMR 0.94, 95% CI 0.74-1.21), and C(12) was increased by 28% (GMR 1.28, 95% CI 0.78-2.10). Ritonavir AUC(0-12) was 20% lower (GMR 0.80, 95% CI 0.54-1.19), C(max) was 15% lower (GMR 0.85, 95% CI 0.55-1.32), and C(12) was 7% lower (GMR 0.93, 95% CI 0.49-1.76). With the exception of indinavir C(max), the changes in indinavir and ritonavir pharmacokinetic parameters observed after fosamprenavir coadministration were not statistically significant. The geometric means of amprenavir AUC(0-12), C(max), and C(12) were 41,517 nghour/ml (95% CI 30,317-56,854 nghr/ml), 5572 ng/ml (95% CI 4330-7170 ng/ml), and 2421 ng/ml (95% CI 1578-3712 ng/ml), respectively.
The combination of indinavir 800 mg-ritonavir 100 mg-fosamprenavir 700 mg twice/day appears to be devoid of a clinically significant drug-drug interaction and should be evaluated as an alternative regimen in salvage HIV treatment. This combination may be suitable as part of a background regimen to optimize the therapeutic benefit of newer classes of antiretroviral agents such as the integrase and coreceptor inhibitors in the treatment of multidrug-resistant viruses.
评估在人类免疫缺陷病毒（HIV）患者中，利托那韦增强的茚地那韦 - 福沙普那韦联合用药的药代动力学相容性。
单中心、非随机、前瞻性、多剂量、两阶段药代动力学研究。
大学研究中心。
8名成年HIV感染患者，他们接受并耐受茚地那韦800毫克 - 利托那韦100毫克，每日两次，至少持续2周。干预措施。在对所有患者进行12小时药代动力学采样后（A期），福沙普那韦（安普那韦的前体药物）700毫克，每日两次，联合给药5天，并在第5天重复进行12小时药代动力学采样（B期）。
测定茚地那韦、利托那韦和安普那韦的药代动力学参数：给药后0至12小时的浓度 - 时间曲线下面积（AUC(0 - 12)）、最大血浆浓度（C(max)）和12小时血浆浓度（C(12)）。对于每个参数，计算几何平均值以及比较B期与A期的几何平均比值（GMR）。茚地那韦C(max)降低了20%（GMR 0.80，95%置信区间[CI] 0.67 - 0.96），AUC(0 - 12)降低了6%（GMR 0.94，95% CI 0.74 - 1.21），C(12)升高了28%（GMR 1.28，95% CI 0.78 - 2.10）。利托那韦AUC(0 - 12)降低了20%（GMR 0.80，95% CI 0.54 - 1.19），C(max)降低了15%（GMR 0.85，95% CI 0.55 - 1.32），C(12)降低了7%（GMR 0.93，95% CI 0.49 - 1.76）。除茚地那韦C(max)外，福沙普那韦联合给药后观察到的茚地那韦和利托那韦药代动力学参数变化无统计学意义。安普那韦AUC(0 - 12)、C(max)和C(12)的几何平均值分别为41,517 ng·小时/毫升（95% CI 30,317 - 56,854 ng·小时/毫升）、5572 ng/毫升（95% CI 4330 - 7170 ng/毫升）和2421 ng/毫升（95% CI 1578 - 3712 ng/毫升）。
茚地那韦800毫克 - 利托那韦100毫克 - 福沙普那韦700毫克，每日两次的联合用药似乎不存在具有临床意义的药物相互作用，应作为挽救性HIV治疗的替代方案进行评估。这种联合用药可能适合作为背景治疗方案的一部分，以优化新型抗逆转录病毒药物（如整合酶和共受体抑制剂）在治疗多重耐药病毒中的治疗效果。
