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Antimicrobial Agents and Chemotherapy, April 2006, p. 1304-1310, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1304-1310.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Tenofovir Disoproxil Fumarate and Ritonavir-Boosted Saquinavir Mesylate Administered Alone or in Combination at Steady State

Gilead Sciences, Inc., Durham, North Carolina

Received 19 September 2005/ Returned for modification 29 November 2005/ Accepted 10 January 2006

A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUC_tau, C_max, and C_tau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a C_tau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUC_tau and C_max levels were not significantly altered, whereas C_tau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.

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