Pharmacokinetic analysis of nevirapine extended release 400 mg once daily vs nevirapine immediate release 200 mg twice daily formulation in treatment-naive patients with HIV-1 infection

Background: VERxVE data showed non-inferior virologic efficacy with extended release nevirapine (NVP-XR) dosed 400 mg once daily (QD) versus immediate release nevirapine (NVP-IR) 200 mg twice daily in a doubleblind, non-inferiority study in treatment-naive HIV-1-positive patients. Objective: To study the pharmacokinetics (PK) of the NVP formulations and identify possible associations with demographic factors. Methods: Patients with viral load >= 1000 copies/mL and CD4+ count > 50- < 400 cells/mm(3) (males) and > 50- < 250 cells/mm(3) (females) at screening received NVP-IR 200 mg QD during a 14-day lead-in and were then stratified by baseline viral load and randomized to NVP-XR or -IR. NVP trough concentrations at steady state (SS) (C-pre,C-ss,C-N) were measured up to week 48 for all participating patients. In a PK sub-study, SS parameters -AUC(0.24), C-max, C-min, and peak-to-trough fluctuation were obtained and analyzed with relative bioavailability assessed at week 4 by plasma collection over 24 h. Results: Trough concentrations were stable from week 4 to week 48 for all patients (n = 1011) with both formulations, with NVP-XR/IR ratios of 0.77-0.82. Overall, 49 patients completed the PK sub-study: 24 XR and 25 IR. NVP-XR showed less peak-to-trough fluctuation (34.5%) than IR (55.2%), and lower AUC(0-24), C-min, C-max, and trough concentrations than IR. However, no effect of SS trough concentrations was found on the virologic response proportion at least up to 1000 ng/mL. No significant association was found between NVP PK and gender, race, and viral load. Conclusion: These data suggest NVP-XR achieves lower but effective NVP exposure compared with NVP-IR.