Comparative single-dose bioavailability study of two 500 mg clarithromycin tablet formulations in healthy volunteers under fasting condition

Jasmina Trojacanec,Dimche Zafirov,Bojan Labachevski,Dobrin Svinarov,Krume Jakjovski,Kalina Gjorgjievska,Nikola Labachevski,Nikola Kolovcevski,Emilija Atanasovska

doi:10.33320/maced.pharm.bull.2019.65.01.003

Abstract

Clarithromycin is a semi-synthetic macrolide antibiotic, chemically 6-0-methylerythromycin, formulated as immediate-release tablets, extended-release tablets, and granules for oral suspension. The objective of this study was to evaluate and compare the relative bioavailability, and therefore the bioequivalence of Clarithromycin 500 mg test formulation versus a reference Klacid® forte 500 mg formulation, following a single dose administration under fasting conditions. The study was a single center, open, single dose, randomized, two-way crossover study in healthy male volunteers, with a wash-out period of one week between study periods. Twenty-four male healthy volunteers, aged 18-49 years were included into study. Blood samples for determination of clarithromycin and 14-OH clarithromycin concentrations were withdrawn at zero (pre-drug administration), 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 and 36 hours post-drug administration. The determination of clarithromycin and 14-OH clarithromycin concentrations in plasma was performed using validated LC/MS/MS method and internal standardization after liquid/liquid extraction with methyl t-butyl ether. The test formulation of clarithromycin, dosed at 500 mg is bioequivalent for primary clarithromycin and 14-OH clarithromycin parameters (Cmax, AUC0-t and AUC0-∞) to the reference formulation after a single oral administration of 500 mg clarithromycin. Both medications were well tolerated with no serious adverse events. Thus, in view of the clinical use, both formulations are exchangeable without restrictions. Keywords: clarithromycin, 14-OH clarithromycin, bioavailability, bioequivalence study, single-dose

Highlights

Clarithromycin is a semi-synthetic macrolide antibiotic, chemically 6-0-methylerythromycin, with molecular formula C38H69NO13, molecular weight of 747.96, formulated as immediate-release tablets, extended-release tablets, and granules for oral suspension
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms, resulting in inhibition of protein synthesis and showing in vitro activity against a variety of aerobic and anaerobic Gram-positive and Gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms
Clarithromycin is used against following microorganisms: aerobic Gram-positive microorganisms (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes), aerobic Gramnegative microorganisms (Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis), Mycoplasma pneumoniae, Chlamydia pneumoniae and Mycobacterium avium complex (MAC) (Dinos, 2017; Fraschini et al, 1993)

Summary

Introduction

Clarithromycin is a semi-synthetic macrolide antibiotic, chemically 6-0-methylerythromycin, with molecular formula C38H69NO13, molecular weight of 747.96, formulated as immediate-release tablets, extended-release tablets, and granules for oral suspension. Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration and food slightly delays the onset of absorption (from 2 to 2,5 hours), with increase of peak plasma concentration by about 24%, but it does not affect the extent of bioavailability (Alkhalidi et al, 2019; Fraschini et al, 1993; Padovan et al, 2012; Quinney et al, 2013). Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration, but does slightly decrease the extent of metabolite formation (Fraschini et al, 1993; Radwan et al, 2019)

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