Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component 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 abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relative to the separate brand-name components administered simultaneously 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 2-day washout period: one A/L/Z combination tablet after an overnight fast, one abacavir 300 mg tablet + one lamivudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after an overnight fast, or one A/L/Z 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 determination of abacavir, lamivudine, and zidovudine serum concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration-time curve (AUC(infinity)) and maximum observed serum concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. GLS ratios and 90% CI for AUC(infinity) and Cmax were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively, for lamivudine; and 0.95 (0.89, 1.02) and 0.96 (0.80, 1.15), respectively, for zidovudine. The extent of absorption of abacavir, 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 abacavir, lamivudine, and zidovudine. These changes, which were consistent with those observed with the individual reference formulations when administered with food, were not considered clinically important. All formulations were well tolerated underfasted and fed conditions.
Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709, USA.
G J
GJ
Yuen
Y
Y
Lou
N F
NF
Thompson
V R
VR
Otto
T L
TL
Allsup
W B
WB
Mahony
H W
HW
Hutman
D000042:Absorption; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004435:Eating / Q000502:physiology*; D005215:Fasting / Q000097:blood / Q000502:physiology; D005260:Female; D006207:Half-Life; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D000099227:Abacavir