A single-dose, randomized, open-label, two-period crossover bioequivalence study of a fixed-dose pediatric combination of lamivudine 40-mg, nevirapine 70-mg, and stavudine 10-mg tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.
BACKGROUND
Because of the lack of suitable pediatric antiretroviral (ARV) agents, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity.


OBJECTIVE
The objective of the present study was to evaluate the bioequivalence of a new pediatric fixed-dose combination (FDC) ARV tablet for oral suspension as compared with individual liquid formulations.


METHODS
The FDC ARV tablet for oral suspension contained lamivudine 40 mg, nevirapine 70 mg, and stavudine 10 mg. This formulation was compared with 4 mL of lamivudine 10 mg/mL, 7 mL of nevirapine 50 mg/5 mL, and 10 mL of stavudine 1 mg/mL. This was an open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose crossover study in 36 Indian male volunteers under fasting conditions. Blood samples were collected before dosing and at 0.167, 0.25, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours after dosing in each period.


RESULTS
The mean (SD) age, weight, and height of the Indian volunteers were 24.78 (5.31) years (range, 18-38 years), 57.06 (8.59) kg (range, 45-77 kg), and 165.14 (5.34) cm (range, 156-176 cm), respectively. The mean (SD) values for T(max), C(max), and AUC(0-t) for the FDC and the individual liquid formulations, respectively, were as follows: lamivudine, 0.71 (0.22) and 0.89 (0.50) hour, 594 (167) and 514 (139) ng/mL, 2382 (617) and 2227 (666) ng /mL per hour; nevirapine, 1.7 (1.1) and 2.5 (1.2) hours, 1248 (275) and 1185 (238) ng/mL, 70,372 (14,869) and 71,278 (17,435) ng/ mL per hour; and stavudine, 0.44 (0.11) and 0.43 (0.11) hour, 348 (82) and 395 (107) ng/mL, and 576 (113) and 631 (142) ng/mL per hour. The ratios and 90% CIs for the least-squares mean Cmax and AUC values were found to be within the prespecified range of 80% to 125% for each component.


CONCLUSIONS
The FDC pediatric formulation of lamivudine, nevirapine, and stavudine was bioequivalent to the individual liquid formulations in these fasting, healthy Indian men.
Monif
Tausif
T
Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd., Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon 122 015, Haryana, India. tausif.monif@ranbaxy.com
Rao Thudi
Nageshwar
N
Koundinya Tippabhotla
Sudhakar
S
Khuroo
Arshad
A
Marwah
Amit
A
Kumar Shrivastav
Vikesh
V
Tandon
Monika
M
Raghuvanshi
Rajeev
R
Biswal
Shibadas
S
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004338:Drug Combinations; D005215:Fasting; D006801:Humans; D007194:India; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018119:Stavudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency
D019380:Anti-HIV Agents; D004338:Drug Combinations; D013607:Tablets; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine