Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis

Abstract

Clarithromycin, a 14-membered ring macrolide, is antimicrobially active against a broad range of gram-positive and certain gram-negative pathogens frequently isolated from softtissue infections and bite wounds (11). Clarithromycin is considered a therapeutic alternative in special cases of minor softtissue infections and penicillin allergy or in cases of nontuberculous mycobacterial skin infections (19,20). High tissue concentrations of the class of the macrolides have been reported previously in the literature (10,13,21). Indeed, intracellular accumulation of macrolides in isolated peripheral blood phagocytes, alveolar macrophages, and tissue culture cells of human origin has been demonstrated previously (9, 16). To date, investigations of in vivo tissue pharmacokinetics (PK) of clarithromycin have been confined to concentrations derived from homogenized biopsy samples of the upper and lower respiratory tract and epithelial lining fluid collection obtained by bronchoalveolar lavage (10, 13, 21). The results derived from homogenized biopsy samples, as frequently used in previous studies, represent an average concentration of all tissue components extracted, including blood cells, intracellular fluid, interstitial fluid, and structural tissue components, and may therefore cause confusion with regard to the actual concentration of an antimicrobial agent in a defined compartment. These data, thus, provide only limited insight into the time course of concentration at the relevant site of most bacterial infections, namely, the extracellular-space fluid. Hence, we used the microdialysis technique, which is capable of the continuous assessment of unbound, i.e., microbiologically active concentrations of clarithromycin in the interstitial-space fluid of soft tissues (15).Knowledge about the concentration-time profiles of free clarithromycin in the interstitial-space fluid of soft tissues can be considered a prerequisite for dosage recommendations in the treatment of extracellularly proliferating bacteria causing soft-tissue infections. Hence, the aim of the present study was to determine free interstitial concentrations of clarithromycin in subcutaneous adipose tissue and skeletal muscle after oral single-and multiple-dose administration to healthy male volunteers. MATERIALS AND METHODSThe study took place at the Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. The study protocol was approved by the local Ethics Committee, and the study was performed in accordance with the Declaration of Helsinki 1964 (including current revisions), the Austrian Drug Law, and the Good Clinical Practice Guidelines.Healthy volunteers. Seven healthy male volunteers between the ages of 25 and 37 years were enrolled into the study. Written informed consent was obtained from each volunteer prior to any study-related investigation or intervention. Each volunteer underwent a screening examination consisting of the following: medical history, physical examination, routine laboratory tests, heart rate, blood pres...

In Vivo Evaluation of Drug-Drug Interaction via Mechanism-Based Inhibition by Macrolide Antibiotics in Cynomolgus Monkeys

“…In addition, treatment periods with macrolides, 3 days, is somewhat shorter than those in human. The plasma concentrations of macrolides in monkey during the treatment of macrolides were estimated to be roughly corresponding to those in each clinical study with ERM, CAM, and AZM; C max and AUC in human were 0.5 g/ml and 2.2 g ⅐ h/ml, 2.2 g/ml, and 10.6 g ⅐ h/ml, and 0.6 g/ml and 3.2 g ⅐ h/ml, respectively (Periti et al, 1989; Jain and Danziger, 2004;Traunmüller et al, 2007). As a result, the extent and the rank order of AUC changes caused by macrolide treatments were almost identical between monkeys and humans.…”

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

“…For example, a clinical microdialysis study performed with six healthy volunteers evaluated the distribution of clarithromycin in muscle and subcutaneous tissue and compared it with unbound plasma concentrations (87). Following a single dose of clarithromycin (250 mg), the ratios of the area under the unbound drug concentration-time curve from 0 to 24 h (fAUC 0 -24 ) in subcutaneous tissue and skeletal muscle versus plasma were 0.29 Ϯ 0.17 and 0.42 Ϯ 0.18, respectively (Fig.…”

Pharmacokinetics of clarithromycin after single intravenous and intracrop bolus administrations to broiler chickens

“…However, the lack of pharmacokinetic studies precludes the rational use of this antimicrobial agent in targeted animal species. Pharmacokinetics of clarithromycin has been studied in human being (Ferrero et al 1990), (Chu et al 1992a) (Traunmuller et al 2007), desert tortoise (Wimsatt et al 1999); foals (Jacks et al 2002), beagle dogs (Zhang et al 2008) and cats (Katayama et al 2012). The present study was designed to characterize pharmacokinetic profile of clarithromycin in a not-yet-studied animal species that is broiler chickens after single intravenous (i.v.)…”