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

Sadler, Brian M.a; Piliero, Peter J.b,c; Preston, Sandra L.c; Lloyd, Peggy P.a; Lou, Yua; Stein, Daniel S.a,d

Clinical Science

Objective To evaluate the safety 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 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.

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 RTV.

From the aDivision of Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA, the bDivision of HIV Medicine and the cDivision of Clinical Pharmacology, Albany Medical College, Albany, New York, USA and the dUniversity of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Correspondence to Dr Daniel Stein, Division of Clinical Pharmacology, GlaxoSmithKline, 5 Moore Dr, 17, 2235, Research Triangle Park, North Carolina, 27709 USA. Tel: +1 919 483 1449; fax: +1 919 483 6380; e-mail: dss94020@GSK.com

Received: 1 November 2000;

revised: 26 February 2001; accepted: 8 March 2001.

Sponsorship: Supported by a grant from GlaxoSmithKline.

Note: This work was presented in part at the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, California, USA, January 30–February 2, 2000 (Abstract 77) and at the First International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, The Netherlands, March 2000 (Abstract 2.10).

© 2001 Lippincott Williams & Wilkins, Inc.