Nijland Hanneke M J, L'homme Rafaëlla F A, Rongen Gerard A, van Uden Peter, van Crevel Reinout, Boeree Martin J, Aarnoutse Rob E, Koopmans Peter P, Burger David M
Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, The Netherlands.
AIDS. 2008 May 11;22(8):931-5. doi: 10.1097/QAD.0b013e3282faa71e.
Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced lopinavir/ritonavir tablets.
A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period.
Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks.
The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.
先前针对健康志愿者的研究表明，利福平与调整剂量的洛匹那韦/利托那韦软胶囊可使洛匹那韦达到足够的暴露量。我们的目的是研究利福平与新推出的洛匹那韦/利托那韦片剂的联合使用情况。
总共40名健康志愿者计划从第1天至第5天开始每日服用一次600毫克利福平。从第6天至第15天，志愿者被随机分为两组，一组每日两次服用600/150毫克的洛匹那韦/利托那韦片剂，另一组每日两次服用800/200毫克的洛匹那韦/利托那韦片剂，两组均每日加服一次600毫克利福平。计划在第15天绘制12小时的药代动力学曲线。在整个研究期间定期进行安全性评估。
11名志愿者作为本研究的第一组开始服药。在第1天至第5天（仅服用利福平）期间未出现重大不适。加服洛匹那韦/利托那韦后，8名志愿者出现恶心和呕吐，1名仅出现恶心，1名仅出现呕吐。在第7天，所有志愿者的天冬氨酸氨基转移酶/丙氨酸氨基转移酶（AST/ALT）水平均升高，第8天，研究提前终止。AST/ALT水平持续上升，并在第9天至第10天达到峰值（2级，n = 2；3级，n = 1；4级，n = 8）。所有数值在6周内恢复正常。
该研究表明，新的洛匹那韦/利托那韦片剂高于标准剂量与利福平联合使用时不良事件发生率较高。未来，不应将这种药物组合用于健康志愿者。当利福平与洛匹那韦/利托那韦在患者中联合使用时，应仔细监测肝功能。
