title: Dose separation does not overcome the pharmacokinetic interaction between fosamprenavir and lopinavir/ritonavir.
abstract: 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.
authors.affiliation: School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ahcorbet@email.unc.edu
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Corbett
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Hsiao-Chuan
authors.initials: HC
authors.lastname: Tien
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Kalvass
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Linh T
authors.initials: LT
authors.lastname: Ngo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Lim
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005663:Furans; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018023:HIV Seronegativity; D006801:Humans; D061466:Lopinavir; D008297:Male; D010755:Organophosphates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D010755:Organophosphates; D011744:Pyrimidinones; D013449:Sulfonamides; D061466:Lopinavir; D019438:Ritonavir; C426859:fosamprenavir