ObjectivesUse of proton pump inhibitors in HIV-infected patients is common. The purpose of this study was to determine the steady-state pharmacokinetics of once-daily (qd) fosamprenavir/ritonavir (FPV/r) and atazanavir/ritonavir (ATV/r) alone and in combination with 20 mg qd omeprazole (OMP) in healthy volunteers. Design and methodsA prospective, open-label, single-site, two-period, crossover pharmacokinetic study was carried out in healthy volunteers. Subjects received either qd FPV/r 1400 mg/200 mg or ATV/r 300 mg/100 mg in the morning for 14 days and then 20 mg OMP in the evening for an additional 7 days. The pharmacokinetics were assessed over 24 h on days 14 and 21. Following a 2-week washout, subjects repeated the process with the other regimen. Trough protease inhibitor (PI) concentrations were taken on day 16 of each period to assess the impact of a single dose of OMP on ATV and amprenavir (APV) concentrations. Plasma ATV and APV pharmacokinetic parameters were assessed by noncompartmental analysis; geometric mean ratios (GMRs; PI 1 OMP/PI; 90% confidence interval) were calculated between days 14 and 21. ResultsNineteen healthy, non-HIV-infected volunteers were evaluated. OMP reduced ATV exposure [area under the concentration curve at 0-24 h (AUC 0-24 h )] and the minimum drug concentration (C min ) by 27% each. In contrast, APV exposure and C min were decreased by 4 and 2%, respectively. Four subjects (21%) experienced greater than 50% declines in both ATV AUC 0-24 h and C min after the addition of OMP; this was not observed in any subject following receipt of FPV/r. No alterations in APV or ATV trough concentrations were observed following a single dose of OMP. ConclusionsThe addition of 20 mg OMP administered in the evening has minimal effect on APV pharmacokinetics. In contrast, ATV pharmacokinetics were altered; a number of ATV-treated subjects experienced pronounced declines in exposures upon the addition of 20 mg OMP administered in the evening, whereas others experienced little to no change.

ObjectiveAn open-label, three-period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF). MethodsThirty-six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty-four-hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady-state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals. ResultsAfter TDF coadministration, APV geometric mean minimum concentration (C min ), maximum concentration (C max ), and area under the plasma concentration-time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C min , C max and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods. ConclusionsIn this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.Keywords: drug interaction, fosamprenavir, tenofovir IntroductionTenofovir disoproxil fumarate (TDF), the prodrug for the nucleotide reverse transcriptase inhibitor tenofovir (TFV), has proved highly effective in the treatment of antiretroviralnaïve and antiretroviral-experienced HIV-infected patients when combined in regimens containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) [1][2][3][4][5][6][7][8]. At the time at which TDF was developed, TDF-PI drug-drug interactions were not expected because TFV is eliminated renally by glomerular filtration and active tubular secretion, whereas PIs are hepatically metabolized [9]. However, drug interaction studies showed that the area under the plasma concentration-time curve (AUC; exposure) DOI: 10.1111DOI: 10. /j.1468DOI: 10. -1293DOI: 10. .2009 (2010), 11, 193-199 193 for TFV increased by 22-32% when TDF was combined with unboosted atazanavir (ATV), ATV boosted by ritonavir (ATV/ RTV), lopinavir (LPV)/RTV, or darunavir (DRV)/RTV, accompanied by 15-20% decreases in ATV and LPV AUCs and a 21% increase in the DRV AUC [10][11][12][13][14]. Although the combination of TDF with fosamprenavir (FPV), the phosphate ester prodrug of the PI amprenavir (APV), has been reported to be effective and well tolerated in HIV-infected patients [4,[15][16][17][18][19], a fo...