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

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Abstract
To evaluate the safety and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV). 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. Relative to APV alone, RTV co-administration resulted in a 3.3- to 4-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration–time curve (AUC τ,ss) and minimum concentration (C min,ss), respectively. APV 900 mg with RTV 100 mg resulted in a 2.09-fold and 6.85-fold increase in the GLS mean AUC τ,ss and C min,ss, respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUC τ,ss (μg • h/mL) was 23.49 (19.32–28.57) with 300 mg RTV and 35.42 (30.46–44.42) with 100 μg RTV, and for the 900 mg APV with 100 mg RTV 47.11 (39.47–61.24). The 450 mg APV C min,ss (μg/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. 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 RTV.