Preclinical safety evaluation of nafithromycin (WCK 4873) with emphasis on liver safety in rat and dog.

Autor: Nandanwar M; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India. Electronic address: mnandanwar@wockhardt.com., Chavan R; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India., Kansagara A; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India., Patel MA; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India., Patel A; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India., Yeole R; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India., Patel M; Wockhardt Research Centre, Chikalthana, Aurangabad, Maharashtra, India.
Jazyk: angličtina
Zdroj: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2021 Jun; Vol. 122, pp. 104889. Date of Electronic Publication: 2021 Feb 12.
DOI: 10.1016/j.yrtph.2021.104889
Abstrakt: Ketolide antibiotics are known to cause hepatic injury. Nafithromycin, a novel lactone ketolide was therefore assessed for hepatic safety through range of preclinical in vitro (metabolic stability, CYP inhibition/induction assays) and in vivo (mass balance and repeat dose toxicity) studies. Repeat-dose toxicity studies in rat and dog revealed that nafithromycin did not cause adverse hematological, biochemical and histopathological changes suggestive of systemic or hepatobiliary safety concern at exposures 3-8 fold higher than targeted therapeutic exposures. The only histological finding noticed was reversible phospholipidosis, mainly in lung and lymphoid organs but not in liver, indicating lower nafithromycin accumulation in liver. This observation was corroborated with lack of biologically relevant elevation of hepatic enzymes linked to hepatic injury. In vitro studies showed that nafithromycin undergoes moderate CYP3A mediated metabolism. Unlike other ketolides, nafithromycin and its metabolites showed weak inhibition of CYP3A isoform and lacked CYP2D6 inhibition. Due to hydrophilic nature, nafithromycin in addition to hepatic clearance is also eliminated unchanged by kidneys in significant amount, thereby minimizing hepatic burden. Based on the scientifically integrated evidences such as moderate metabolism, weak CYP inhibition, lack of CYP induction, minimal accumulation in liver, nafithromycin showed promising hepatic safety profile suitable for its intended community-based usage.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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