title: Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species.
abstract: CD101 is a novel semisynthetic echinocandin with antifungal activity againstCandidaandAspergillusspp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats, dogs, cynomolgus monkeys, and chimpanzees are presented. CD101 consistently exhibited very low clearance, a modest volume of distribution at steady state (Vss), and a long half-life (t1/2) across all species tested. In mouse, rat, dog, cynomolgus monkey, and chimpanzee, CD101 clearance was 0.10, 0.47, 0.30, 0.41, and 0.06 ml/min/kg, respectively;Vsswas 206, 1,390, not determined, 597, and 400 ml/kg, respectively; andt1/2was 25, 39, 53, 40, and 81 h, respectively. CD101 demonstrated a lower clearance and correspondingly longer half-life than those of anidulafungin, with more pronounced differences in higher species (anidulafungint1/2, 8 h in cynomolgus monkey and 30 h in chimpanzee). In the rat, tissue/plasma area under the concentration-time curve (AUC) ratios, in descending order, were 4.62 (kidney), 4.33 (lung), 4.14 (liver), 3.87 (spleen), 1.09 (heart), and 0.609 (brain), indicating that CD101 exposure relative to plasma levels was comparable for major organs (approximately 4-fold higher in tissue than in plasma), with the exception of the heart and brain. Biliary elimination of intact CD101 was the predominant route of excretion; the mean cumulative amount of CD101 excreted into the bile and feces over the course of 5 days accounted for 22.6% and 27.7% of the total dose administered, respectively. There were no sex differences in the pharmacokinetics of CD101. Given its low clearance, long half-life, and wide tissue distribution, CD101 once weekly is expected to provide appropriate systemic levels for treatment and prevention of invasive fungal infections.
authors.affiliation: Cidara Therapeutics, Inc., San Diego, California, USA vong@cidara.com.
authors.forename: Voon
authors.initials: V
authors.lastname: Ong
authors.affiliation: Seachaid Pharmaceuticals, Durham, North Carolina, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: James
authors.affiliation: Seachaid Pharmaceuticals, Durham, North Carolina, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.affiliation: Seachaid Pharmaceuticals, Durham, North Carolina, USA.
authors.forename: B Radha
authors.initials: BR
authors.lastname: Krishnan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry; D001923:Brain Chemistry; D004285:Dogs; D054714:Echinocandins / Q000097:blood / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D065669:Hepatobiliary Elimination / Q000502:physiology*; D066237:Intestinal Elimination / Q000502:physiology*; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009206:Myocardium / Q000737:chemistry; D002679:Pan troglodytes; D051381:Rats; D013154:Spleen / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; C000621306:CD101 echinocandin; D054714:Echinocandins
keywords: CD101; Candida; antifungal agents; echinocandin; pharmacokinetics; preclinical drug studies