Safety and Pharmacokinetics of Higher Doses of Caspofungin in Healthy Adult Participants

• Published in: Journal of clinical pharmacology Vol. 51; no. 2; pp. 202 - 211
• Main Authors: Migoya, Elizabeth M., Mistry, Goutam C., Stone, Julie A., Comisar, Wendy, Sun, Peng, Norcross, Alisha, Bi, Sheng, Winchell, Gregory A., Ghosh, Kalyan, Uemera, Naoto, Deutsch, Paul J., Wagner, John A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2011; SAGE Publications; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; Area Under Curve; caspofungin; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Echinocandins - administration & dosage; Echinocandins - adverse effects; Echinocandins - pharmacokinetics; Female; Half-Life; high dose; Humans; Lipopeptides; Male; Middle Aged; pharmacokinetics; safety; tolerability; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270010374853

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 AUC0‐∞ 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 AUC0–24 was 227.4 μg·h/mL, peak concentration was 20.9 μg/mL, and trough concentration was 4.7 μg/mL. Beta‐phase t1/2 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.