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Nevirapine Concentrations With Once- Versus Twice-Daily Dosing
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Nevirapine concentrations--including maximum and minimum concentration--were moderately lower but adequate with once-daily extended-release nevirapine (NVP XR) compared with twice-daily immediate-release nevirapine (NVP IR), according to pharmacokinetic analysis of the VERxVE trial comparing these two doses [1]. Trough concentrations with both regimens were stable through 48 weeks, though nevirapine exposure fluctuated less with NVP XR than with NVP IR.
The double-blind, double-dummy VERxVE noninferiority trial compared NVP XR at a dose of 400 mg once daily with NVP IR taken at 200 mg twice daily in 1011 antiretroviral-naive people, both with tenofovir/emtricitabine [2]. Study participants could not have resistance to nonnucleosides, tenofovir, emtricitabine, or lamivudine. At enrollment all study participants had a viral load above 1000 copies/mL and a CD4 count from 50 to 400 in men (85% of study participants) and from 50 to 250 in women. At the 48-week point, 80% in the NVP XR group and 79% in the NVP IR group had a viral load below 50 copies. The two groups did not differ in rates of adverse events, severe events, events leading to discontinuation, or lipid changes.
The pharmacokinetic (PK) analysis involved 50 of 1011 study participants at 14 of 215 trial sites who underwent 24-hour plasma sampling at study week 4 for standard concentration measurements plus peak-to-trough fluctuation. These PK study participants and a larger group also had trough measurements at week 48. Forty-nine people in the PK group completed the study, 24 on NVP XR and 25 on NVP IR.
At the 4-week point, geometric mean 24-hour area under the concentration-time curve (AUC0-24), maximum concentration (Cmax), minimum concentration (Cmin), and peak-to-trough fluctuation were all moderately lower in the once-daily group than in the twice-daily group (adjusted geometric mean ratios in parentheses):
-- AUC0-24 once vs twice daily: 75,323 vs 96,176 ng x h/mL (76.72%)
-- Cmin once vs twice daily: 2581 vs 3121 ng/mL (82.69%)
-- Cmax once vs twice daily: 3767 vs 5464 ng/mL (68.94%)
-- Peak-to-trough fluctuation once vs twice daily: 34.5% vs 55.2% (62.5%)
In a comparison of 376 people taking once-daily nevirapine and 321 taking twice-daily nevirapine, geometric mean trough at week 48 was lower with the once-daily dose (3433 vs 4465 ng/mL, geometric mean ratio 76.9%).
A second trough comparison involved 448 people taking once-daily nevirapine and 438 taking the twice-daily dose. Geometric mean trough at all study visits between week 4 and week 48 was 3354 ng/mL in the once-daily group and 4107 ng/mL in the twice-daily group (geometric mean ratio 81.66%).
The investigators proposed that "these data (with efficacy results) suggest NVP XR compared with NVP IR achieved lower but effective NVP exposure." Demographic factors did not directly affect PK results. The FDA licensed NVP XR for treatment of adults in March 2011.
References
1. Yong CL, Gathe J, Rockstroh J, et al. Pharmacokinetic analysis of nevirapine extended release 400 mg qd vs immediate release 200 mg bid in patients with HIV-1 infection. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1721.
2. Gathe J, Bogner J, Santiago S, et al. Comparison of 48 week efficacy and safety of 400 mg QD nevirapine extended release formulation (Viramune XR) versus 200 mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada in antiretroviral naive HIV-1 infected patients (VERxVE). XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract THLBB202.
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