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Steady State Evaluation of Two Extended Release (XR) Nevirapine (NVP) Tablets 400 mg QD Compared with Immediate Release (IR) NVP Tablets 200 mg BID in HIV-1 Infected Patients
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Reported by Jules Levin
ICAAC Sept 11-15 2009 San Francisco
A. QUINSON1, K. ARASTEH2, A. PLETTENBERG3, J. BOGNER4, F. BOUE5, J. M. LIVROZET6, M. WI TT7, E. VAN STEENBERGE1, C. SAUCE1, C. L. YONG1, S. MACHA1, J. WU1, L. WALDHAUSER1, F. J. MENSA1, F. BERGER1, J. STERN1, P. ROBINSON1, M. BATTEGAY 8
1Boehringer Ingelheim, Ridgefield, CT; 2Epimed GmbH, Berlin, Germany; 3Ifi Studien und Projekte GbR, Hamburg, Germany; 4University of Munich, Munich, Germany; 5Antoine Béclère Hospital, Clamart, France; 6Edouard Herriot Hospital, Lyon, France; 7UCLA Medical Center, Torrance, CA; 8University Hospital Basel, Basel, Switzerland
Author Conclusions
Administration of NVP XR 400 mg QD resulted in extended absorption and reductions in peak levels at steady state while attaining similar troughs as NVP IR.
NVP XR 25% tablets exhibited better bioavailability and lower variability than the NVP XR 20% formulation.
Both NVP XR formulations were safe and well tolerated.
No virologic failures were observed.
Based on these findings, NVP XR 25% was selected for further development.
Abstract
Background
NVP IR 200 mg BID is part of combination therapy for HIV-1 infection. Boehringer Ingelheim developed two NVP XR tablet formulations (20% and 25%) to be given QD.
Methods:
This was an international, open label, multistage, parallel group, crossover study. Patients (≤50 c/mL) who had been treated for >12 weeks with a stable regime based on IR 200 mg BID were switched to NVP XR (Group A 25%, Group B 20%) 400 mg QD for 19 days. Plasma samples at steady state after IR and XR were collected over a 24-h period.
Results
In 48 patients treated with XR, NVP was absorbed slowly (tmax 6.7 - 8.6 h vs ≤2 h for IR). The NVP Cmin of XR was comparable to that of IR while the Cmax was lower. Relative bioavailability (based on AUC0-24) of XR to IR was 80% and 71% for the 25% and 20% tablets. The incidence of AEs was low and comparable in both groups. No virologic failures were observed.
Conclusions
Both NVP XR formulations were safe and well tolerated. Administration of NVP XR 400 mg QD resulted in extended absorption and reductions in peak levels at steady state while attaining similar troughs. The XR 25% formulation exhibited better bioavailability and variability than the XR 20% and was selected for further development.
INTRODUCTION
Adherence is important in preventing treatment failure and drug resistance in HIV therapy (1,2). Once daily (QD) dosing is preferred to improve compliance. Viramune® (NVP IR) 200 mg tablets are given twice daily (BID) as part of combination therapy for HIV-1 infection. Boehringer Ingelheim developed two extended release formulations of NVP (identified as XR 25% and XR 20%) to allow QD dosing as a means of improving therapy with Viramune.
This study compared the relative bioavailability at steady state of each NVP XR formulation with that of NVP IR in subjects infected with HIV-1.
METHODS
This clinical trial was an international, open label, multistage, parallel group, crossover study. Eligible subjects were males and females infected with HIV-1 fully suppressed to <50 c/mL at screening who had been treated for >12 weeks with a stable regimen containing NVP IR 200 mg BID without protease inhibitors.
After entering the study, subjects continued treatment with NVP IR 200 mg BID for an additional 3 days (reference treatment). Then subjects were switched to one of the two NVP XR 400 mg QD formulations (25% or 20%) for 19 days (test treatment). Plasma samples were taken for 24 h following the last dose of each treatment.
Trial Endpoints:
· AUC0-24 --- to define relative bioavailability
· tmax, Cmax, Cmin, Cmax/Cmin ratio -- as other pharmacokinetic parameters
· Adverse events (AEs), clinical laboratory, viral load at each visit (every 3 days).
RESULTS
Demographics
Demographic characteristics were similar in treatment groups.
Table 1. Demographic characteristics of study subjects
*Mean (standard deviation)
Pharmacokinetics
The relative bioavailability compared with NVP IR (based on gMean ratios of AUC0-24) was 80% (90% CI 73.0 - 86.7) for NVP XR 25% and 71% (90% CI 63.3 - 86.7) for NVP XR 20%. Group B (XR 20%) showed greater inter-individual variability in plasma concentrations of NVP than Group A (XR 25%).
Compared with NVP IR (Table 2), both NVP XR formulations resulted in: longer tmax, lower Cmax, and similar Cmin (89.6%)(90%CI 80.6 - 99.6) for NVP XR 25%, but lower Cmin (75.1%) (90%CI 65.1 - 85.6)for NVP XR 20%.
NVP concentration-time profiles of both XR formulations exhibited less fluctuation than for NVP IR (Figures 1 and 2).
*Mean (% coefficient of variation)
Safety
The frequency of patients with AEs during 19 days treatment with NVP XR was low and similar with both XR formulations (14/24 subjects with XR 25% vs 10/24 subjects with XR 20%). Adverse events were usually mild (DAIDS grade 1; 12/24 subjects with XR 25% vs 9/24 subjects with XR 20%). No subjects experienced severe or serious AEs. One subject in each
group had an AE which was considered drug-related - diarrhea with XR 25% and increased HIV RNA (blip) with XR 20%. The most frequently reported AE was nasopharyngitis (0/24 subjects with XR 25% vs 4/24 with XR 20%).
No clinically relevant changes in laboratory values (including transaminase elevations) were observed. There were no virologic failures.
References
1. Flaharty KK, Hall D, Scherer J, Jelaska A. HIV-1 genotypic resistance in subjects treated with nevirapine and efavirenz in combination with stavudine and lamivudine The 2NN study. 1100.1288. 16 December 2003.
2. Flaharty KK, Hall D, Scherer J, MacGregor T, Jelaska A, Robinson P. Nevirapine and efavirenz plasma concentrations and correlation with viral load and virologic resistance in subjects from the 2NN study. 1100.1288. 22 January 2004.
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