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

Objective: To evaluate the safely and pharmacokinetic interaction between a mprenavir (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 bo th 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 mi nimum concentration (C-min,C-ss), respectively. APV 900 mg with RN 100 mg r esulted 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) w ith 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 m g APV. The most common AEs were mild and included diarrhea, nausea/vomiting , oral parasthesias, and rash. The triglyceride and cholesterol increased s ignificantly from RTV exposure. Conclusion: Adding RTV to APV resulted in clinically and statistically sign ificant increases in APV AUC and C-min with variable effects on maximum con centration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg (C) 2001 Lippincott Williams & Wilkins.