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Single- and Multiple-Dose Administration of Caspofungin in Patients With Hepatic Insufficiency: Implications for Safety and Dosing Recommendations

From Merck & Co, Inc, Whitehouse Station, New Jersey (Mr Mistry, Dr Migoya, Dr Deutsch, Dr Winchell, Mr Hesney, Ms Li, Ms Bi, Dr Stone) and Clinical Pharmacology Associates, Miami, Florida (Ms Dilzer, Dr Lasseter).

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single-dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple-dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration-time profile over the interval of last quantifiable point to infinity (AUC_0-) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32-1.86) in the single-dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04-1.39) for day 14 area under the concentration-time profile calculated over the interval 0 to 24 hours (AUC_0-24h) following multidose. The AUC_0- GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51-2.06) following 70 mg; AUC_0-24h GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90-1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate hepatic insufficiency.

Key Words: MK-0991 • caspofungin • pharmacokinetics • hepatic insufficiency

Address for correspondence: Goutam C. Mistry, MSc, Department of Clinical Pharmacology, Merck Research Laboratories, RY34-A500, Rahway, NJ 07065.

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