icon-folder.gif   Conference Reports for NATAP  
 
  EACS - 12th European AIDS Conference
November 11-14, 2009
Cologne, Germany
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ASSESSMENT OF THE STEADY STATE PK PARAMETERS OF TWO EXTENDED RELEASE (XR) NEVIRAPINE (NVP) TABLETS 400 MG AND 300 MG QD COMPARED WITH IMMEDIATE RELEASE (IR) NVP TABLETS 200 MG BID IN HIV-1 INFECTED PATIENTS - THE ERVIR STUDY
 
 
  ASSESSMENT OF THE STEADY STATE PK PARAMETERS OF TWO EXTENDED RELEASE (XR) NEVIRAPINE (NVP) TABLETS 400 MG AND 300 MG QD COMPARED WITH IMMEDIATE RELEASE (IR) NVP TABLETS 200 MG BID IN HIV-1 INFECTED PATIENTS - THE ERVIR STUDY
 
Reported by Jules Levin
EACS Nov 13 2009 Cologne
 
M. Battegay1, K. Arasteh2, A. Plettenberg3, J. Bogner4, N. Brockmeyer5, O. Degen6, F. Boue7, J.M. Livrozet8, E. Van-steenberge9, C.L. Yong10, J. Wu10, F.J. Mensa10, L. Waldhauser9, J. Steffgen9, F. Berger9, J. Stern10, P. Robinson10, A.M. Quinson10
1University Hospital Basel, Infectious Diseases & Hospital Epidemiology, BASEL, Switzerland, 2Epimed GmbH, Berlin, Germany, 3Ifi Studien und Projekte GbR, Hamburg, Germany, 4University of Munich, Munich, Germany, 5University of Bochum, Bochum, Germany, 6University Hamburg, Hamburg, Germany, 7Hospital Antoine Beclere, Clamart, France, 8Hospital Edouard Herriot, Lyon, France, 9Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, 10Boehringer Ingelheim Pharm. Inc., Ridgefield, United States
 
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 400 XR 25% tablets exhibited better bioavailability and lower variability than other XR formulations.
 
NVP XR formulations demonstrated similar rates of AEs by dose and nearly all were mild.
 
No virologic failures were observed.
 
Based on these findings, NVP 400 XR 25% was selected for further development.
 
ABSTRACT
 
Background

NVP IR 200 mg BID is widely used as part of combination therapy for HIV-1 infection.
 
Boehringer Ingelheim has developed two NVP XR tablet formulations (20% and 25%) of 300 mg and 400 mg each to be given QD.
 
Methods
The ERVIR study was an international, open label, multistage, parallel group, crossover study. HIV-1 infected patients (viral load ≤50 c/mL) treated for >12 weeks with an stable regimen based on Viramune® 200 mg BID (IR) were eligible. After measuring steady state PK parameters of Viramune® for 3 days, subjects were switched for 19 days to NVP XR 400 mg QD (Group A 25% or Group B 20%) or 300 mg QD (Group C 25% or Group D 20%). Plasma samples at steady-state after IR and XR were collected over a 24h period.
 
Results
In 92 patients treated with XR, NVP was absorbed slowly (tmax,ss 6.7-8.6 h, vs ≤2 h for IR). The Cmin,ss of XR 400 mg was comparable to that of IR while the Cmax,ss was lower. Relative bioavailability (based on AUC0-24) of XR to IR was 80% and 71% for the XR 25% and 20% of 400 mg, respectively; and was 90% and 84% for the XR 25% and 20% of 300 mg, respectively. The inter-subject coefficient of variation of AUC0-24 was 27% and 44% for the XR 25% and 20% of 400mg, respectively.
 
The incidence of adverse events (AEs) was low and comparable in all groups. No virologic failures were observed.

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Conclusions
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 400 mg XR 25% formulation exhibited better bioavailability and less variability than the XR 20% and was selected for the pivotal phase III study VERxVE.
 
INTRODUCTION
Adherence is important in preventing treatment failure and drug resistance in HIV therapy (1,2). Once daily (QD) administration of drugs improve adherence, compared to multiple doses/day. Viramune® (NVP IR) 200 mg tablets are given twice daily (BID) as part of combination therapy for HIV-1 infection. Boehringer Ingelheim developed two investigational extended release formulations of NVP (identified as XR 25% and XR 20%) given in 400 or 300 mg to evaluate QD dosing. This study compared the relative bioavailability at steady state of each investigational XR formulation with that of NVP IR in subjects infected with HIV-1.
 
METHODS
The ERVIR study was an international, open label, multistage, parallel group, crossover clinical trial. Eligible subjects were males and females infected with HIV-1 fully suppressed to <50 cps/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 (baseline assessment). Then subjects were switched to one of the four NVP XR QD formulations: 400 mg XR 25% (Group A), 400 mg XR 20% (Group B), 300 mg XR 25% (Group C) and 300 mg XR 20% (Group D) for 19 days (test treatment). Plasma samples were taken for 24 h following the last dose of each treatment.
 
Key pharmacokinetic (PK) endpoints were: AUC0-24 (to define relative bioavailability), tmax, Cmax, Cmin, Cmax/Cmin ratio. AEs, clinical laboratory and viral load were clinical endpoints.
 
RESULTS
 
Demographics

Demographic characteristics were similar in treatment groups.
 

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Pharmacokinetics
The relative bioavailability compared with NVP IR (based on gMean XR / IR ratios of AUC0-24) were 80% (90% CI 73-86.7) for Group A, 71% (90% CI 63.3 - 79.6) for Group B, 90% (90% CI 80.3 - 101.4) for Group C and 84% (90% CI 78 - 89.9) for Group D (Groups C and D are dose-adjusted). Group B showed greater inter-individual variability in plasma concentrations of NVP comparing to Group A (Table 2). Compared with NVP IR, both NVP XR 400 mg formulations (Groups A and B) resulted in longer tmax and lower Cmax. Cmin,ss was similar in Group A (gMean XR / IR ratio of Cmin,ss: 89.6% [90%CI 80.6 - 99.6]) and lower in Group B (gMean XR / IR ratio of Cmin,ss: 75.1% [90%CI 65.1 - 85.6]).
 
The relative exposure of NVP 300 mg QD compared with NVP IR 200 mg BID (based on dose unadjusted gMean XR / IR ratios) for Groups C and D were 68% and 62% for AUC0-24, and were 75% and 63% for Cmin,ss, respectively.
 

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Safety
The frequency of patients with AEs during 19 days treatment with NVP XR was low and similar within treatment groups (Table 3). Adverse events were usually mild. No subjects experienced DAIDS Grade 3 or 4. One subject experienced a serious adverse event (SAE) which required hospitalization; this SAE was not considered drug-related (left sensorineural hearing loss). Five subjects had an AE which was considered drug-related (all but one were mild). The most frequently reported AE was nasopharyngitis. No clinically relevant changes in laboratory values were observed. Of the 789 determinations of viral load performed during the study, 22 resulted in low-grade detectable viral loads (blips) among 17 subjects. However, there were no virologic failures confirmed (defined as ≥ 2 consecutive viral load >50 copies/mL).
 

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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.