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.
Full conference title:
- ICAAC 41st