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-τ [112 ± 6.2 μg· h/ml QD; 115 ± 6.4 μg·h/ml 2 × BID; QD/BID 0.98; 90% confidence interval (CI) 0.89,1.07]. The maximum observed plasma concentration within a dosing interval (Cmax) was 49% higher for QD (9.5 ± 2.7 μg/ml) versus BID (6.3 ± 1.7 μg/ml) and the pre-dose plasma concentration (Ctrough) was 57% lower for QD (1.6 ± 1.1 μg/ml) versus BID (3.8 ± 1.3 μg/ml). The LSM decrease in viral load from baseline to day 7 was 1.0 ± 0.14 log10 (n = 18) for QD and 1.4 ± 0.2 log10 (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 Ctrough but not Cmax 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.