Pharmacokinetics, pharmacodynamics and safety of once-daily versus twice-daily dosing with enfuvirtide in HIV-infected subjects

Objective: To investigate the pharmacokinetics, safety/tolerability and antiviral activity of enfuvirtide administered once-daily (QD) versus. twice-daily (BID). Design: An open-label, randomized, multiple dose, two-period crossover study comparing 180 mg enfuvirtide, two injections QD versus 90 mg enfuvirtide, two injections, BID. Methods: Steady-state intensive pharmacokinetic samples were obtained on days 7 and 14. Results: Thirty-seven subjects received at least one dose of enfuvirtide. Thirty-three subjects completed both dosing periods. The regimens were bioequivalent based on the ratio of geometric mean area under the curve (AUC)(0-tau) [112 +/- 6.2 mu g. h/ml QD; 115 +/- 6.4 mu g.h/ml 2 x BID; QD/BID 0.98; 90% confidence interval (CI) 0.89,1.07]. The maximum observed plasma concentration within a dosing interval (C-max) was 49% higher for QD (9.5 +/- 2.7 mu g/ml) versus BID (6.3 +/- 1.7 mu g/ml) and the pre-dose plasma concentration (C-trough) was 57% lower for QD (1.6 +/- 1.1 mu g/ml) versus BID (3.8 +/- 1.3 mu g/ml). The LSM decrease in viral load from baseline to day 7 was 1.0 +/- 0.14 log(10) (n = 18) for QD and 1.4 +/- 0.2 log(10) (n = 17) for BID (LSM difference 0.385; P = 0.07). Linear regression analysis suggested that decline in viral load up to day 7 was associated with C-trough but not C-max or AUC. There were no significant differences in adverse events between the two dosing regimens. Conclusions: Administration of enfuvirtide 180 mg QD results in bioequivalence compared with 90 mg BID based on AUC with a similar short-term safety profile, but a trend towards a weaker antiretroviral effect. Larger and longer-term studies are needed to determine if 180 mg once daily is an effective dosing alternative for enfuvirtide. (C) 2006 Lippincott Williams & Wilkins.