Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen.
OBJECTIVE
Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) are preferred agents for treatment of HIV-1 infection in adults. This study evaluated the pharmacokinetics (PK) and bioequivalence of an investigational coformulation of EFV/FTC/TDF (test) single-tablet regimen compared with the commercially available individual dosage forms (EFV+FTC+TDF; reference treatment) in healthy subjects.


METHODS
Subjects were randomized to 1 of 2 treatment sequences (test-->reference or reference-->test) in an open-label crossover study design. Study drug was administered under fasted conditions, and serial blood samples were obtained over 504 hours after oral administration of each treatment. Formulation bioequivalence was assessed in accordance with the US Food and Drug Administration bioequivalence criteria.


RESULTS
Forty-eight subjects were enrolled, and 45 completed the study, with all study treatments being generally well tolerated. For EFV (n = 44), the geometric mean ratios (90% confidence interval [CI]) for maximum concentration (C(max)), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC(0-last)), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC(inf)) were 99.9 (93.4 to 107), 95.7 (90.5 to 101), and 95.2 (88.9 to 102), respectively. For FTC (n = 45), the geometric mean ratios (90% CI) for C(max), AUC(0-last), and AUC(inf) were 88.8 (84.0 to 93.9), 98.0 (94.9 to 101), and 98.0 (94.9 to 101), respectively. For tenofovir (n = 45), the geometric mean ratios (90% CI) for C(max), AUC(0-last), and AUC(inf) were 91.5 (84.6 to 98.8), 99.3 (91.0 to 108), and 100 (93.2 to 108), respectively.


CONCLUSIONS
The coformulation of EFV/FTC/TDF is bioequivalent to administration of its individual components.
Mathias
Anita A
AA
Gilead Sciences, Foster City, CA 94404, USA. anita.mathias@gilead.com
Hinkle
John
J
Menning
Mark
M
Hui
James
J
Kaul
Sanjeev
S
Kearney
Brian P
BP
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000068679:Emtricitabine; D005215:Fasting; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013607:Tablets / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068698:Tenofovir; D013810:Therapeutic Equivalency
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D013607:Tablets; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz