Pharmacokinetics of extended-release clarithromycin in patients with Mycobacterium ulcerans infection

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-adm...

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Bibliographic Details
Published in:	Scientific reports Vol. 14; no. 1; pp. 19963 - 7
Main Authors:	Klis, Sandor-Adrian, Stienstra, Ymkje, Abass, Kabiru M., Abottsi, Justice, Mireku, Samuel O., Alffenaar, Jan-Willem, van der Werf, Tjip S.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28-08-2024 Nature Publishing Group Nature Portfolio
Subjects:	631/154/436 631/154/436/1729 692/699/255/1318 692/700/565/1436/2774 Adult Aged Anti-Bacterial Agents - administration & dosage Anti-Bacterial Agents - pharmacokinetics Area Under Curve Buruli Ulcer - drug therapy Buruli Ulcer - microbiology Clarithromycin Clarithromycin - administration & dosage Clarithromycin - pharmacokinetics Delayed-Action Preparations - pharmacokinetics Drug dosages Drug metabolism Female Humanities and Social Sciences Humans Male Middle Aged multidisciplinary Mycobacterium ulcerans Mycobacterium ulcerans - drug effects Pharmacokinetics Rifampin Rifampin - administration & dosage Rifampin - pharmacokinetics Rifampin - therapeutic use Science Science (multidisciplinary) Streptomycin Tandem Mass Spectrometry Young Adult
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Summary:	Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC–MS/MS in 30 study participants—20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA C max was 0.4 mg/L—and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in C max and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF C max or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-70890-w