Effect of Hepatic Insufficiency on the Pharmacokinetics of Caspofungin

J. STONE1, S. HOLLAND1, S. LI1, P. WICKERSHAM1, P. DEUTSCH1, G. WINCHELL1, M. HESNEY1, S. BI1, M. FRIEL1, G. MISTRY1, S. DILZER2, K. LASSETER2

Author address: 

1Merck Research Laboratories, West Point, PA, 2Clinical Pharmacology Associates, Miami, FL.

Abstract: 

Background: Caspofungin (CancidasTM, MK-0991, L-743,872) is a parenteral antifungal agent that inhibits the synthesis of 1,3 b-D glucan, an essential component of the fungal cell wall. Methods: The effect of hepatic insufficiency (HI) on caspofungin pharmacokinetics was evaluated in two Phase I studies: (A) A pilot single-dose (70 mg) study in subjects with mild (Child-Pugh 5 to 6, n=8) and moderate (Child-Pugh 7 to 9, n=8) HI compared to historical healthy controls (n=24); and (B) A definitive, 14-day, multiple-dose study in subjects with mild (n=8) and moderate (n=8) HI and age-gender-weight-matched healthy subjects. In study (2), subjects with mild HI and all controls received 50 mg daily with a 70-mg loading dose on Day 1, while subjects with moderate HI received a reduced dose of 35 mg daily following the 70-mg loading dose. Results: Modest-to-moderate increases in caspofungin plasma concentrations were seen with mild HI. The geometric mean ratio (GMR) (90% CI) for mild HI/controls was 1.55 (1.32, 1.86) for AUC(0-infinity) in study (A) and 1.21 (1.04, 1.39) for Day 14 AUC(0-24hr) in study (B). These increases in AUC were judged not to be clinically significant. Moderate HI had a larger effect than mild HI. In study (A), the GMR (90% CI) for moderate HI/controls was 1.76 (1.51, 2.06) for AUC(0-infinity). The dose reduction for moderate HI evaluated in study (B) provided a similar AUC to that obtained in controls receiving the standard dose. The GMR (90% CI) for moderate HI/controls was 1.07 (0.90, 1.28) for Day 14 AUC(0-24hr) in study (B). Conclusions: No dosage adjustment is recommended for patients with mild HI. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate HI.
2001

abstract No: 

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Full conference title: 

ICAAC 41st
    • ICAAC 41st