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Antimicrobial Agents and Chemotherapy, August 2006, p. 2756-2761, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01006-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dose Separation Does Not Overcome the Pharmacokinetic Interaction between Fosamprenavir and Lopinavir/Ritonavir

Amanda H. Corbett,1* Kristine B. Patterson,2 Hsiao-Chuan Tien,3 Leslie A. Kalvass,1 Joseph J. Eron,2,3 Linh T. Ngo,2 Michael L. Lim,4 and Angela D. M. Kashuba1,3

Schools of Pharmacy,1 Medicine,2 UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,3 GlaxoSmithKline, Research Triangle Park, North Carolina 277094

Received 4 August 2005/ Returned for modification 26 September 2005/ Accepted 25 May 2006

Previous investigations have shown a significant negative two-way drug interaction between fosamprenavir (FPV) and lopinavir/ritonavir (LPV/RTV) in both human immunodeficiency virus (HIV)-infected patients and seronegative volunteers. This randomized, nonblinded, three-way crossover study of HIV-seronegative adult volunteers investigated dose separation and increased doses of RTV as a means to overcome the interaction between FPV and LPV/RTV. Eleven HIV-seronegative volunteers were given FPV plus LPV/RTV at 700 mg plus 400/100 mg every 12 hours (q12h) simultaneously for 10 days and then randomized to receive each of three 7-day treatments in one of six possible sequences, as follows: FPV plus LPV/RTV at 700 mg plus 400 mg/100 mg q12h simultaneously, FPV/RTV at 700 mg/100 mg q12h plus LPV/RTV at 400 mg/100 mg q12h, with doses separated by 4 h, and FPV/RTV at 1,400 mg/200 mg in the morning plus LPV/RTV at 800 mg/200 mg in the evening. Pharmacokinetic sampling was performed on day 8 of each treatment, and samples were analyzed for FPV, amprenavir (APV), LPV, and RTV concentrations by high-performance liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR [with 95% confidence intervals]) for the 4- and 12-h dose separation strategies compared to simultaneous administration were calculated for the areas under the concentration-time curves from 0 to 24 h. Compared to simultaneous administration, RTV exposures increased with both 4-h and 12-h dose separation strategies (GMR, 5.30 [3.66 to 7.67] and 4.45 [3.09 to 6.41], respectively). LPV exposures also significantly increased with both 4-h and 12-h dose separation strategies (GMR, 1.76 [1.34 to 2.32] and 1.43 [1.02 to 2.01], respectively). However, both the 4- and 12-h strategies resulted in greater reductions in APV exposure (0.67 [0.54 to 0.83] and 0.77 [0.59 to 0.99], respectively) compared to simultaneous administration. Additional investigations are warranted to determine the optimal dosing of FPV with LPV/RTV.

* Corresponding author. Mailing address: School of Pharmacy, 3317 Kerr Hall, CB#7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 843-2280. Fax: (919) 962-0644. E-mail: ahcorbet{at}email.unc.edu.

Antimicrobial Agents and Chemotherapy, August 2006, p. 2756-2761, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01006-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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