Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers

被引:61
作者
Sadler, BM
Piliero, PJ
Preston, SL
Lloyd, PP
Lou, Y
Stein, DS
机构
[1] GlaxoSmithKline, Div Clin Pharmacol, Res Triangle Pk, NC 27709 USA
[2] Albany Med Coll, Div HIV Med, Albany, NY 12208 USA
[3] Albany Med Coll, Div Clin Pharmacol, Albany, NY 12208 USA
[4] Univ N Carolina, Sch Med, Chapel Hill, NC USA
关键词
protease inhibitors; amprenavir; ritonavir; safety; pharmacokinetics; drug interaction;
D O I
10.1097/00002030-200105250-00009
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objective: To evaluate the safely and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV). Methods: Three open-label, randomized, two-sequence, multiple-dose studies having the same design (7 days of APV or RTV alone followed by 7 days of both drugs together) used 450 or 900 mg APV with 100 or 300 mg RTV every 12 h with pharmacokinetic assessments on days 7 and 14. Safety was monitored as clinical adverse events (AEs) and laboratory abnormalities. Results: Relative to APV alone, RTV co-administration resulted in a 3.3- to l-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration-time curve (AUC(tau .ss)) and minimum concentration (C-min,C-ss), respectively. APV 900 mg with RN 100 mg resulted in a 2.09-fold and 6.85-fold increase in the CLS mean AUC(tau ,ss) and C-min,C-ss, respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUC(tau ,ss) (mug.h/mL) was 23.49 (19.32-28.57) with 300 mg RTV and 35.42 (30.46-44.42) with 100 mug RTV and for the 900 mg APV with 100 mg RTV 47.11 (39.47-61.24). The 450 mg APV C-min,C-ss (mug/ml) were 1.32 (1.05-1.67) and 2.01 (1.70-2.61), and 2.47 (2.08-3.32) for 900 mg APV. The most common AEs were mild and included diarrhea, nausea/vomiting, oral parasthesias, and rash. The triglyceride and cholesterol increased significantly from RTV exposure. Conclusion: Adding RTV to APV resulted in clinically and statistically significant increases in APV AUC and C-min with variable effects on maximum concentration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg (C) 2001 Lippincott Williams & Wilkins.
引用
收藏
页码:1009 / 1018
页数:10
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