拉替拉韦 400 mg 每日两次与达芦那韦/利托那韦 800/100 mg 每日一次联合治疗方案的药代动力学研究：HIV-1 感染患者。

Pharmacokinetic study of dual therapy with raltegravir 400 mg twice daily and Darunavir/Ritonavir 800/100 mg once daily in HIV-1-infected patients.

机构信息

Infectious Diseases Service, Hospital Clínic, IDIBAPS, Barcelona, Spain.

出版信息

Ther Drug Monit. 2013 Aug;35(4):552-6. doi: 10.1097/FTD.0b013e31828d50ef.

DOI:10.1097/FTD.0b013e31828d50ef

PMID:23851911

Abstract

BACKGROUND

Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients.

METHODS

This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits.

RESULTS

Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients.

CONCLUSIONS

Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.

摘要

背景

新型抗逆转录病毒药物联合方案是避免核苷类逆转录酶抑制剂（NRTIs）相关毒性以及为具有一定 NRTIs 耐药性的患者提供完整有效治疗方案的理想选择。然而，目前有关这些方案药代动力学（PK）特征的数据有限。我们在感染 HIV-1 的患者中探索了拉替拉韦（RAL）400mg 每日两次和达芦那韦/利托那韦（DRV/RTV）800/100mg 每日一次的 PK 特征。

方法

这是一项试点、开放标签、固定序列、前瞻性、单中心单臂 PK 研究。由于 NRTIs 的毒性或耐药突变，主治医生选择了一种 NRTI 节省方案，该方案包括每日一次的 DRV/RTV 800/100mg 和每日两次的 RAL 400mg。所有患者均为 RAL 和 DRV 初治且无蛋白酶抑制剂突变证据。治疗至少 15 天后，患者入院进行 24 小时 PK 研究。所有研究访视时均进行实验室检测以评估疗效和安全性。

结果

共纳入 15 例患者。DRV 的几何平均值为 AUC0-24 68,730ng·h·mL[95%置信区间（CI）：58,970-86,480]，Ctrough 1330ng/mL（95%CI：1110-1760；野生型和耐药 HIV-1 株的 IC50 分别为 55 和 550ng/mL），Cmax 7630ng/mL（95%CI：6740-9000），t1/2 为 10.9 小时（95%CI：9.20-13.99）。RAL 的几何平均值为 AUC0-12 3050ng·h·mL（95%CI：2530-5180）；Ctrough 40ng/mL（95%CI：30-80），Cmax 970ng/mL（95%CI：840-2270），t1/2 为 2.68 小时（95%CI：1.97-4.40）。未观察到皮疹或实验室检查异常等不良反应。在第 24 周时，所有患者的 HIV-1 病毒载量均低于 37 拷贝/mL。