title: Bioavailability of extended-release nevirapine 400 and 300 mg in HIV-1: a multicenter, open-label study.
abstract: BACKGROUND
  Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy.
  
  
  OBJECTIVE
  The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets.
  
  
  METHODS
  This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ≤50 copies/mL), and treated for ≥12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC(0-24,ss), C(max,ss), and C(min,ss), analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for C(max). Adverse events (AEs) and viral loads were monitored.
  
  
  RESULTS
  Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC(0-24,ss) values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0-86.7; P = 0.544], 71.0% [90% CI, 63.3-79.7; P = 0.956], 90.3% [90% CI, 80.4-101.4; P = 0.044], and 83.7% [90% CI, 77.9-89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. C(max,ss) values were lower with all NVP XR formulations compared with NVP IR. For C(min,ss), NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% (P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, >50 copies/mL over 2 consecutive readings) were observed.
  
  
  CONCLUSIONS
  Extent of bioavailability was lower and t(max,ss) was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. C(min,ss) with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arasteh
authors.forename: Andreas
authors.initials: A
authors.lastname: Plettenberg
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Bogner
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Livrozet
authors.forename: Mallory D
authors.initials: MD
authors.lastname: Witt
authors.forename: Erik
authors.initials: E
authors.lastname: Mossdorf
authors.forename: Chan-Loi
authors.initials: CL
authors.lastname: Yong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Sreeraj
authors.initials: S
authors.lastname: Macha
authors.forename: Frank
authors.initials: F
authors.lastname: Berger
authors.forename: Jerry
authors.initials: J
authors.lastname: Stern
authors.forename: Patrick
authors.initials: P
authors.lastname: Robinson
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Quinson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D019829:Nevirapine