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).


METHODS
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 microg x h/ml QD; 115 +/- 6.4 microg x 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 (Cmax) was 49% higher for QD (9.5 +/- 2.7 microg/ml) versus BID (6.3 +/- 1.7 microg/ml) and the pre-dose plasma concentration (Ctrough) was 57% lower for QD (1.6 +/- 1.1 microg/ml) versus BID (3.8 +/- 1.3 microg/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.
Thompson
Melanie
M
AIDS Research Consortium of Atlanta, Atlanta, Georgia 30308, USA. drmt@mindspring.com
DeJesus
Edwin
E
Richmond
Gary
G
Wheeler
David
D
Flaherty
John
J
Piliero
Peter
P
True
Andrea
A
Chiu
Yu-Yuan
YY
Zhang
Ying
Y
McFalls
Emily
E
Miralles
G Diego
GD
Patel
Indravadan H
IH
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage* / Q000009:adverse effects; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide