title: Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.
abstract: Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.
authors.affiliation: Merck Research Laboratories, PO Box 2000, RY34-A500, Rahway, NJ, USA. elizabeth_migoya@merck.com
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Migoya
authors.forename: Goutam C
authors.initials: GC
authors.lastname: Mistry
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stone
authors.forename: Wendy
authors.initials: W
authors.lastname: Comisar
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Alisha
authors.initials: A
authors.lastname: Norcross
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Winchell
authors.forename: Kalyan
authors.initials: K
authors.lastname: Ghosh
authors.forename: Naoto
authors.initials: N
authors.lastname: Uemera
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Deutsch
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D000077336:Caspofungin; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D055666:Lipopeptides; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin