ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2006, p. 3157–3159 0066-4804/06/$08.00⫹0 doi:10.1128/AAC.00093-06 Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Vol. 50, No. 9
Interaction between Fosamprenavir, with and without Ritonavir, and Nevirapine in Human Immunodeficiency Virus-Infected Subjects Edwin DeJesus,1 Peter J. Piliero,2 Kim Summers,3 Mary Beth Wire,4 Daniel S. Stein,5 Amanda Masterman,6 Yu Lou,4 Sherene S. Min,4 and Mark J. Shelton4* Orlando Immunology Center, Orlando, Florida1; Boehringer Ingelheim, Ridgefield, Connecticut2; San Antonio VA, San Antonio, Texas3; GlaxoSmithKline, Research Triangle Park, North Carolina4; Sanofi-Aventis, Bridgewater, New Jersey5; and GlaxoSmithKline, Mississauga, Ontario, Canada6 Received 23 January 2006/Returned for modification 15 May 2006/Accepted 11 June 2006
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. 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 ⫽ 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.
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 ⬍400 copies/ml at screening. Women had to be of non-childbearing potential or
TABLE 1. Steady-state plasma APV PK parameter estimates and treatment comparisons a APV PK estimates 关geometric mean (95% CI)兴 Parameter
Current study NVP ⫹ FPV (n ⫽ 17)
NVP ⫹ FPV ⫹ RTV (n ⫽ 17)
FPV treatment comparisons 关GLS mean ratio (90% CI)兴
Historical control
b
FPV ⫹ RTV (n ⫽ 82)
FPV (n ⫽ 40)
NVP ⫹ FPV vs. FPV
NVP ⫹ FPV ⫹ RTV vs. FPV
30.0 (24.7–36.4) 16.7 (14.8–18.8) 33.7 (31.5–36.1) 0.668 (0.555–0.803) 0.890 (0.772–1.03) AUC(0-)(g · h/ml) 11.1 (9.11–13.6) 3.58 (3.05–4.19) 5.06 (4.30–5.96) 4.75 (4.21–5.37) 5.24 (4.92–5.59) 0.752 (0.632–0.896) 0.965 (0.847–1.10) Cmax (g/ml) 0.192 (0.155–0.237) 1.56 (1.27–1.92) 0.295 (0.243–0.358) 1.93 (1.77–2.09) 0.650 (0.498–0.850) 0.809 (0.684–0.956) C (g/ml)
NVP ⫹ FPV ⫹ RTV vs. NVP ⫹ FPV 2.70 (2.25–3.24) 1.42 (1.17–1.71) 8.11 (6.86–9.60)
a Doses: NVP, 200 mg of NVP BID; FPV, 1,400 mg of FPV BID; FPV ⫹ RTV, 700 mg of FPV BID plus 100 mg of RTV BID. NRTIs were coadministered in the current study as well as in some subjects included in the FPV historical control population. b The historical control groups were comprised of HIV-infected and healthy adult subjects enrolled in all previous GSK protocols where full plasma APV PK profiles were collected following administration of 1,400 mg of FPV BID or 700 mg of FPV BID plus 100 mg of RTV BID.
* Corresponding author. Mailing address: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709. Phone: (919) 4835062. Fax: (919) 315-4276. E-mail:
[email protected]. 3157
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NOTES
ANTIMICROB. AGENTS CHEMOTHER. TABLE 2. Steady-state plasma NVP PK parameter estimates and treatment comparisons a NVP PK estimates 关geometric mean (95% CI)兴
Parameter
AUC(0-)(g · h/ml) Cmax (g/ml) C (g/ml) a
NVP treatment comparisons 关GLS mean ratio (90% CI)兴
NVP (n ⫽ 17)
NVP ⫹ FPV (n ⫽ 17)
NVP ⫹ FPV ⫹ RTV (n ⫽ 17)
NVP ⫹ FPV vs. NVP
NVP ⫹ FPV ⫹ RTV vs. NVP
55.4 (46.9–65.5) 6.11 (5.29–7.06) 4.00 (3.25–4.92)
71.7 (58.0–88.6) 7.65 (6.21–9.41) 5.36 (4.35–6.59)
63.2 (48.7–81.9) 6.91 (5.35–8.92) 4.86 (3.67–6.44)
1.29 (1.19–1.40) 1.25 (1.14–1.37) 1.34 (1.21–1.49)
1.14 (1.05–1.24) 1.13 (1.03–1.24) 1.22 (1.10–1.35)
Doses: NVP, 200 mg of NVP BID plus NRTIs; FPV, 1,400 mg of FPV BID plus NRTIs; FPV ⫹ RTV, 700 mg of FPV BID plus 100 mg of RTV plus NRTIs.
Plasma samples were analyzed for APV concentrations byAdvion Biosciences (Ithaca, NY) using a validated highperformance liquid chromatography with tandem mass spectrometric (HPLC-MS-MS) detection method following solidphase extraction. Plasma samples were analyzed for NVP concentrations by Quest Pharmaceutical Services, LLC (Newark, DE), using a validated HPLC-MS-MS method following liquid-liquid extraction. The pharmacokinetic (PK) analysis of the plasma NVP and APV concentration-time data by noncompartmental methods was conducted using WinNonlin Professional version 4.1 (Pharsight Corp., Mountainview, CA). All plasma NVP and APV pharmacokinetic parameters were log transformed prior to statistical analysis. Pharmacokinetic parameters were compared using analysis of variance in SAS (version 8.2; SAS Corp., Cary, NC) using mixed linear models. Historical control pharmacokinetic data for 1,400 mg of FPV BID and 700 mg of FPV /100 mg of RTV BID without concurrent NVP was used for plasma APV pharmacokinetic comparisons. For all treatment comparisons, the ratios of geometric least squares (GLS) means and associated 90% confidence intervals (CIs) were estimated for plasma APV and NVP PK parameters. Summaries of steady-state plasma pharmacokinetic parameters and treatment comparisons are pre-
sented in Table 1 for APV and in Table 2 for NVP. The median steady-state plasma NVP concentration-time curves are presented by treatment on a linear scale in Fig. 1. The most commonly reported adverse events included nausea (39%), diarrhea (33%), headache (22%), rash (22%), and loose stools (17%). No severe or serious adverse events, deaths, or pregnancies were reported. One subject withdrew prematurely from the study during period 2 due to a fear of phlebotomy and mild nausea. Compared to historical control data, coadministration of 1,400 mg of FPV BID with 200 mg of NVP BID significantly decreased the plasma APV area under the plasma concentration-time curve over the dosing interval () at steady state (AUC0-) by 33%, the maximum concentration of drug in serum (Cmax) by 25%, and the plasma concentration at the end of (C) by 35%; whereas, coadministration of 700 mg of FPV BID plus 100 mg of RTV BID with 200 mg of NVP BID did not significantly alter plasma APV AUC0- or Cmax and resulted in a minor (19%) decrease in C. These results were expected based on existing drug interaction data for FPV (with and without RTV) and efavirenz, a CYP3A4 inducer of similar potency as NVP (10). The historical control groups for the APV comparison were
FIG. 1. Median steady-state plasma NVP concentration-time curves presented by treatment on a linear scale.
VOL. 50, 2006
comprised of HIV-infected and healthy adult subjects enrolled in previous GSK protocols, where full plasma APV PK profiles were collected following administration of 1,400 mg of FPV BID or 700 mg of FPV BID plus 100 mg of RTV BID. Although the majority of the PK data in the control was from healthy subjects, plasma APV pharmacokinetics following administration of FPV or FPV plus RTV are similar between HIV-infected patients and healthy subjects (Y. Kim, C. Hu, M. Wire, K. Moore, M. Sale, and the GW433908 Study Group, Abstr. 5th Int. Wkshp. Clin. Pharmacol. HIV Ther., abstr. 7.5, 2004). Although historical controls are not the ideal comparator group, the results of this study are in agreement with expectations from existing drug interaction data for APV and FPV (with and without RTV) and efavirenz (10). Both FPV and RTV are CYP3A4 inhibitors. Plasma NVP trough concentrations were increased by 34% and 22% following coadministration with 1,400 mg of FPV BID and 700 mg of FPV BID plus 100 mg of RTV BID, respectively, in this study. The magnitude of increase in NVP exposure observed in this study is unlikely to be clinically significant (2, 3, 5, 6, 9). This study was designed to evaluate the steady-state pharmacokinetic interaction between 1,400 mg of FPV BID and 200 mg of NVP BID and between 700 mg of FPV BID plus 100 mg of RTV BID and 200 mg of NVP BID in order to make dosing recommendations for the combinations. Although the effect of NVP on plasma APV pharmacokinetics following coadministration of 1,400 mg of FPV once a day plus 200 mg of RTV once a day was not evaluated in this study, data with efavirenz suggest that additional RTV may be necessary in this regimen (10). Because of significant reductions in plasma APV exposure, which could reduce the efficacy of FPV, NVP should not be coadministered with 1,400 mg of FPV BID. The results of this study support the recommendation that no dosing adjustments are required when NVP is coadministered with 700 mg of FPV plus 100 mg of RTV BID.
NOTES
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We thank S. Shaw for assistance with the programming and L. Kirby for clinical monitoring support.
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