title: Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis.
abstract: SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, includingCandidaspp. andAspergillusspp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases.In vitrodisposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0-∞) andCmaxSCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indicesCmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0-24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases.
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA steve.wring@scynexis.com.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wring
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Randolph
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: SeongHee
authors.initials: S
authors.lastname: Park
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: George
authors.initials: G
authors.lastname: Abruzzo
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Flattery
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: Graig
authors.initials: G
authors.lastname: Garrett
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peel
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Outcalt
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Powell
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Trucksis
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Angulo
authors.affiliation: SCYNEXIS, Inc., Jersey City, New Jersey, USA.
authors.forename: Katyna
authors.initials: K
authors.lastname: Borroto-Esoda
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002177:Candidiasis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D002264:Carboxylic Acids / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D005936:Glucans / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D000935:Antifungal Agents; D002264:Carboxylic Acids; D005936:Glucans; D010616:Phenanthrenes
keywords: SCY-078; candidemia; fungal disease; pharmacokinetics