Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

Abstract

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...

Overexpression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD) provides protection against AZT- or 3TC-induced endothelial dysfunction

“…Drug levels measured in the plasma of treated animals were within the reported C min and C max for humans [AZT: Cmin = 3 ng/mL and Cmax = 635 ng/mL; 3TC: Cmin = 78 ng/mL and Cmax = 1195 ng/mL (van Praag et al, 2002); TDF: Cmin = 52 ng/mL and Cmax = 262 ng/mL (Luber et al, 2010)]. For the most part, drug levels were not altered between strains.…”

Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

“…The low dose of TAF (25 mg) versus the dose of TDF (300 mg), enabled by its greater plasma stability (versus that of TDF) and greater permeation into target cells (versus the permeation of TFV), results in circulating TFV levels ϳ90% lower than those of TDF in the setting of normal renal function. Although the plasma exposures of TFV resulting from a dose of TAF of 25 mg were expected (and, indeed, shown) to be higher in subjects with severe renal impairment than in controls with normal renal function, they were nonetheless expected to be lower than the TFV exposures historically seen with a dose of TDF of 300 mg in subjects with normal renal function as a part of various antiretroviral regimens (Table 4) (15)(16)(17)(18)(19)(20)(21). This additional comparison using reference TFV exposures from TDF is important, since the safety profile of TDF has been well established on the basis of extensive clinical experience in patients (22).…”