Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption.
A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand-name components administered concurrently and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 5- to 7-day washout period: one lamivudine/zidovudine combination tablet after an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet simultaneously after an overnight fast, or one lamivudine/zidovudine combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for the determination of lamivudine and zidovudine plasma concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals for the ratio of least squares (LS) means for the lamivudine and zidovudine area under the plasma concentration-time curve (AUC infinity) and maximum observed plasma concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC infinity) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC infinity and Cmax were 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent of absorption of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of lamivudine and zidovudine. These changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.
Moore
K H
KH
Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA.
Shaw
S
S
Laurent
A L
AL
Lloyd
P
P
Duncan
B
B
Morris
D M
DM
O'Mara
M J
MJ
Pakes
G E
GE
D000042:Absorption; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004435:Eating; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D006261:Headache / Q000139:chemically induced; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D013607:Tablets; D013810:Therapeutic Equivalency; D015215:Zidovudine / Q000009:adverse effects / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D013607:Tablets; D019259:Lamivudine; D015215:Zidovudine