Assessment of the bioequivalence of two formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions: A single-dose, randomized, open-label, two-period, two-way crossover study in healthy Jordanian male volunteers

Abstract

Background: Clarithromycin extended-release tablets are indicated for the treatment of adults with acute maxillary sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae; acute bacterial exacerbation of chronic bronchitis due to H influenzae, Haemophilus parainfluenzae, M catarrhalis, or S pneumoniae; or community acquired pneumonia due to H influenzae, H parainfluenzae, M catarrhalis, S pneumoniae, Chlamydia pneumoniae, or Mycoplasma pneumoniae.Objective: This study was conducted to assess the bioequivalence of test and reference formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions.Methods: This was a single-dose, randomized, openlabel, 2-period, 2-way crossover study with a 1-week washout period between doses. Separate bioequivalence studies (fasting and fed) were performed in 2 groups of healthy male Jordanian volunteers. Eighteen blood samples were obtained from each volunteer over 38 hours after drug administration. Clarithromycin concentrations were determined in plasma using a validated high-performance liquid chromatography method with electrochemical detection. Pharmacokinetic parameters of clarithromycin (Cmax, Tmax, AUC0-t, AUC0-∞, λz [firstorder elimination rate constant], and t½) were calculated and analyzed statistically. Tolerability was assessed based on changes in vital signs and laboratory tests, and by questioning subjects about adverse events.Results: Thirty-eight volunteers each participated in the fasting and fed studies. The mean ages of participants in the fasting and fed studies were 26.7 and 27.6 years, respectively; their mean weight was 71.2 and 70.9 kg and mean height was 171.3 and 179.0 cm. Under fasting conditions, the arithmetic mean (SD) Cmax was 569.4 (189.3) ng/mL for the test formulation and 641.2 (202.0) ng/mL for the reference formulation, with a geometric mean ratio of 0.88. The arithmetic mean AUC0-t was 8602.9 (4105.1) and 8245.3 (4122.4) ng · h/mL in the respective formulations, with a geometric mean ratio of 1.06. The arithmetic mean Tmax was 8.0 (5.6) and 6.1 (3.8) hours. In the fed study, the Cmax and AUC of both formulations were significantly increased relative to the fasting study (P < 0.05). The arithmetic mean Cmax of the 2 formulations was 1183.0 (637.5) and 1199.6 (496.3) ng/mL, with a geometric mean ratio of 0.93. The arithmetic mean AUC0-t was 12,981.2 (7849.0) and 11,822.9 (5790.2) ng · h/mL, with a geometric mean ratio of 1.06. The arithmetic mean Tmax was 5.7 (2.8) and 6.7 (2.5) hours. The 90% CI for the ratio (test:reference) of log-transformed Cmax and AUC values was within the acceptance range of 0.80 to 1.25. The 2 formulations were both well tolerated, and no adverse events were reported during the study.Conclusions: In these fasting and fed studies in healthy male Jordanian volunteers, the 2 formulations of clarithromycin extended-release 500-mg tablets were found to be bioequivalent according to the US Food and Drug Administration regulatory definition. Administration with food significantly increased the rate and extent of absorption of both products, with no significant effect on their bioequivalence.