Pharmacokinetics and tolerability of extended-release clarithromycin

Background: Clarithromycin is a semisynthetic macrolide that exhibits broad -spectrum activity against gram-positive, gram-negative, and atypical respi ratory tract and skin/skin structure pathogens, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of Mycobacterium avium complex infection and pept ic ulcers due to H pylori. Objective: In this article, we review the results of 3 studies of the stead y-state pharmacokinetic profiles of clarithromycin and 14(R)-hydroxy-clarit hromycin after multiple oral once-daily doses of 500-mg extended-release (E R) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithrom ycin conducted in adults with acute maxillary sinusitis (AMS) and acute exa cerbation of chronic bronchitis (AECB). Methods: In the 3 pharmacokinetic studies, multiple-dose regimens of clarit hromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and f emale volunteers, were evaluated. The effect of administration in nonfastin g versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studie s conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin tablets twice daily or 1000 mg (2 x 500 mg) ER clarithrom ycin tablets once daily for 7 days (AECB) or 14 days (AMS). Results: Bioavailability of the ER clarithromyin tablet administered with f ood was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and acti ve metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting cond itions. Compared with the IR tablet, administration of the ER tablet result ed in significantly lower (P < 0.05) clarithromycin peak plasma concentrati on (C-max), delayed time to C-max, and lower degree of concentration fluctu ation, confirming its in vivo extended-release characteristics. The most fr equently reported adverse events (AEs) in the phase III clinical trials wer e diarrhea, abnormal taste, and nausea acid were generally mild or moderate . The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation (P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste (P = 0.004). Conclusions: The results from the 3 pharmacokinetic studies reviewed demons trate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in pha se III clinical trials. The ER tablet should be taken with food to maximize bioavailability, The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.