Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species

Abstract

CD101 is a novel semisynthetic echinocandin with antifungal activity against Candida and Aspergillus spp. 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; Vss was 206, 1,390, not determined, 597, and 400 ml/kg, respectively; and t1/2 was 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 (anidulafungin t1/2, 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.

Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model

“…CD101 is a next-generation echinocandin drug candidate in clinical development. Because of substantially reduced toxicity due to chemical stability and enhanced PK properties, CD101 can be safely dosed at much higher levels than other echinocandin drugs ( 25 , 33 , 34 ). Based on mouse PK and human phase I clinical trial data, 20 mg/kg in mice is considered equivalent to a human therapeutic dose.…”

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

“…New glucan synthase targeting echinocandins that are in development may also produce differing cellular responses. As stated above, rezufungin can reportedly penetrate into deep tissue lesions better than micafungin [31] and exhibits a long half-life in pharmacokinetic studies [54,55]. An orally-active glucan synthase inhibitor, SCY-078 (Scynexis, Jersey City, NJ), exhibits activity against some otherwise-resistant FKS mutants [56], likely a result of a slightly different binding spot on the Fks protein [57].…”

Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata

“…New glucan synthase targeting echinocandins that are in development may also produce differing cellular responses. As stated above, rezufungin can reportedly penetrate into deep tissue lesions better than micafungin [ 31 ] and exhibits a long half-life in PK studies [ 58 , 59 ]. An orally-active glucan synthase inhibitor, SCY-078 (Scynexis, Jersey City, NJ, USA), exhibits activity against some otherwise-resistant FKS mutants [ 60 ], likely a result of a slightly different binding spot on the Fks protein [ 61 ].…”