Interaction between Fosamprenavir, with and without Ritonavir, and Nevirapine in Human Immunodeficiency Virus-Infected Subjects

Abstract

Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.Fosamprenavir (FPV; GW433908) has been approved for the treatment of human immunodeficiency virus (HIV)-infected adult patients. FPV, the phosphate ester prodrug of the HIV-1 protease inhibitor amprenavir (APV), is rapidly and extensively converted to APV in vivo (11). Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated safety and efficacy in the treatment of HIV. Chronic administration of NVP leads to induction of cytochrome P450 (CYP450) metabolism (1). This study was designed to determine the steady-state drug-drug interaction between FPV and NVP. Because another NNRTI, efavirenz, was known to decrease APV exposure in other studies (4, 7, 10) and because of safety concerns with NVP in HIV-seronegative individuals (8), this study was conducted in HIV-infected subjects who were receiving and tolerating well an antiretroviral regimen of NVP and nucleoside reverse transcriptase inhibitors (NRTIs).Adult male and female HIV-infected subjects who had received stable antiretroviral regimens containing nevirapine at a dose of 400 mg/day for at least 12 weeks were eligible to participate if they had HIV RNA levels of Ͻ400 copies/ml at screening. Women had to be of non-childbearing potential or agree to acceptable contraceptive measures if they were of child-bearing potential. Breastfeeding and pregnant women were excluded. All subjects were informed of all aspects of the study and had to provide written informed consent approved by their local institutional review board prior to study participation. Subjects continued their prior NRTIs throughout the study, but other HIV-1 protease inhibitors and additional NNRTIs were prohibited.This study was conducted as an open-label, single-sequence, three-period, steady-state drug interaction study at three sites in the United States (GlaxoSmithKline [GSK] protocol APV10014). All subjects were receiving 200 mg of NVP twice a day (BID) in period 1. During period 2, 1,400 mg of FPV BID was added to the antiretroviral regimen and continued for 14 days. During period 3, the FPV dose was changed to 700 mg of FPV plus 100 mg of ritonavir (RTV) BID and continued for 14 days. There was no washout period between study treatments.On the final day of each treatment period, 15 serial wholeblood samples were collected over 12 h (t ϭ 0, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h after the morning dose) for the determination of plasma NVP and APV concentrations. AUC (0-) (g · h/ml) 11.1 (9.11-13.6) 30.0 (24.7-36.4) 16.7 (14.8-18.8) 33.7 (31.5-36.1) 0.668 (0.5...

Impact of nevirapine or efavirenz co‐administration on ritonavir‐boosted amprenavir pharmacokinetics in HIV‐infected patients

“…This divergence could be explained by the limitations of our pharmacokinetic study design which are concentration data mainly clustered around 12 h after last dose, each subject contributed only one to two samples and a limited number of patients treated [12]). No increase in amprenavir clearance was found in combination with nevirapine or efavirenz which suggest that ritonavir 100 mg twice daily is sufficient to compensate efavirenz or nevirapine induction according to previous studies [5][6][7][8]. According to these results, the mean values of the trough plasma concentrations are within the amprenavir target therapeutic range (0.8-3 mg/L [13]) recommended for antiretroviral treatment-naive patients in all groups of patients, although fosamprenavir/ritonavir dosage (700 mg/100 mg twice daily) in combination with nevirapine or efavirenz was not increased.…”

“…The regimen approved in the European Union is 700 mg/100 mg (fosamprenavir/ ritonavir) twice daily [3]. Previous studies investigated the pharmacokinetic interaction between amprenavir and efavirenz [5][6][7] or nevirapine [8]. However, nevirapine and efavirenz could decrease amprenavir plasma concentrations as nevirapine and efavirenz are potent inductors of cytochrome P450 (CYP) isoenzymes, such as CYP3A4, the enzyme responsible for amprenavir metabolism [4].…”

“…The combinations of fosamprenavir/ritonavir and non-nucleoside reverse transcriptase inhibitors (NNRTI), such as nevirapine or efavirenz, are often guided by HIV resistance assays in patients who had undergone previous antiretroviral therapy. These studies were performed with seronegative individuals [5,6] and/or with amprenavir and not fosamprenavir [7] and/or with a limited number of patients [7,8]. Previous studies investigated the pharmacokinetic interaction between amprenavir and efavirenz [5][6][7] or nevirapine [8].…”

Clinical management of drug interaction with antiretroviral agents

“…A number of desirable outcomes may be accomplished by 'ritonavir boosting', which include the following: reduced doses or dosing frequencies of the inhibited protease inhibitors [20]; increased drug exposure and trough concentrations of the protease inhibitors to improve the inhibitory quotients and antiviral activity [21]; and counteraction of the induction effects of other drugs (e.g. adding low-dose ritonavir to some protease inhibitors when they are used in combination with efavirenz or nevirapine) [22,23].…”

Clinical Relevance of Drug Interactions in HIV-Infected Patients Receiving Antiretroviral Therapy

“…Table 6. Clinical relevant drug interactions due to enzyme induction mediated by NNRTIs (DeJesus et al, 2006;DHHS, 2011;Krikorian & Rudorf, 2005;Young, 2005) Methadone and efavirenz (nevirapine). Efavirenz and nevirapine may reduce methadone area under curve (AUC) by 57% and 46%, respectively.…”