Hugen P W, Burger D M, ter Hofstede H J, Koopmans P P, Stek M, Hekster Y A, Reiss P, Lange J M
Department of Clinical Pharmacy; Department of General Internal Medicine, University Medical Centre St. Radboud Nijmegen and National AIDS Therapy Evaluation Centre, Academical Medical Centre, Amsterdam, The Netherlands.
J Acquir Immune Defic Syndr. 2000 Nov 1;25(3):236-45. doi: 10.1097/00126334-200011010-00005.
In antiretroviral therapy, to improve compliance the need is increasing to develop regimens that combine potency and safety with convenient dosing. The objective of our study was to find a once-daily dosing regimen of a HIV-protease inhibitor, indinavir (IDV), by combining it with ritonavir (RTV). In the study, 12 healthy volunteers took a single IDV dose of 800 mg on day 1. Plasma and urine sampling was done for 12 hours. From day 2 to day 21, participants took RTV liquid 200 mg (group A) or 400 mg (group B) once daily. Repeated pharmacokinetic sampling was performed over the course of 24 hours, after single doses of indinavir 400 mg (day 15), 800 mg (day 18), and 1200 mg (day 21). The best dosage regimen in this pharmacokinetic study was selected based on efficacy and tolerability criteria. The study comprised 10 male and 2 female healthy volunteers, mean age, 25 years (range, 18-50 years), mean weight, 70 kg (range, 52-83 kg). One male participant discontinued on day 8 due to influenza. All other participants completed the study without the occurrence of serious adverse events. RTV inhibited indinavir plasma clearance by 51% to 70%, leading to increased and prolonged IDV exposure. Renal clearance was influenced by the addition of RTV and dosage increments of IDV. The efficacy criterion was best fulfilled by 1200 mg IDV/400 mg RTV, whereas this combination performed most poorly on tolerability criteria. Based on the single dose data, a once-daily regimen of IDV with a low dose of RTV is possible. The best dosage regimen to start with among those studied here appears to be 1200 mg IDV/400 mg RTV, which could be decreased at steady state to 800 IDV/400 RTV or 1200 IDV/200 RTV if toxicity occurs. Steady-state pharmacokinetic data of once-daily IDV/RTV regimens in HIV-infected patients are warranted.
在抗逆转录病毒治疗中，为提高依从性，开发将强效性、安全性与便捷给药方式相结合的治疗方案的需求日益增加。我们研究的目的是通过将HIV蛋白酶抑制剂茚地那韦（IDV）与利托那韦（RTV）联合使用，找到一种每日一次给药的方案。在该研究中，12名健康志愿者在第1天单次服用800mg IDV。进行了12小时的血浆和尿液采样。从第2天至第21天，参与者每日一次服用200mg RTV液体（A组）或400mg RTV液体（B组）。在单次服用400mg茚地那韦（第15天）、800mg茚地那韦（第18天）和1200mg茚地那韦（第21天）后，在24小时内进行了重复的药代动力学采样。根据疗效和耐受性标准，在该药代动力学研究中选择了最佳给药方案。该研究包括10名男性和2名女性健康志愿者，平均年龄25岁（范围18 - 50岁），平均体重70kg（范围52 - 83kg）。一名男性参与者因流感在第8天退出。所有其他参与者完成了研究，未发生严重不良事件。利托那韦使茚地那韦的血浆清除率降低了51%至70%，导致茚地那韦的暴露增加且持续时间延长。利托那韦的加入和茚地那韦剂量的增加影响了肾脏清除率。1200mg IDV/400mg RTV最符合疗效标准，而该组合在耐受性标准方面表现最差。基于单剂量数据，低剂量利托那韦与茚地那韦每日一次给药方案是可行的。在此研究的给药方案中，最佳起始给药方案似乎是1200mg IDV/400mg RTV，如果出现毒性反应，在稳态时可降至800mg IDV/400mg RTV或1200mg IDV/200mg RTV。有必要获取HIV感染患者中茚地那韦/利托那韦每日一次给药方案的稳态药代动力学数据。
