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Antimicrobial Agents and Chemotherapy, April 2004, p. 1272-1280, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1272-1280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disposition of Caspofungin, a Novel Antifungal Agent, in Mice, Rats, Rabbits, and Monkeys

Punam Sandhu,* Xin Xu,{ddagger} Peter J. Bondiskey,§ Suresh K. Balani, Michael L. Morris,{dagger} Yui S. Tang, Alisha R. Miller, and Paul G. Pearson||

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486

Received 10 October 2003/ Returned for modification 5 November 2003/ Accepted 24 November 2003

The metabolism, excretion, and pharmacokinetics of caspofungin (Cancidas; Merck & Co., Inc.) were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. Caspofungin had a low plasma clearance (0.29 to 1.05 ml/min/kg) and a long terminal elimination half-life (11.7 h to 59.7 h) in all preclinical species. The elimination kinetics of caspofungin were multiphasic and displayed an initial distribution phase followed by a dominant ß-elimination phase. The presence of low levels of prolonged radioactivity in plasma was observed and was partially attributable to the chemical degradation product M0. Excretion studies with [3H]caspofungin indicated that the hepatic and renal routes play an important role in the elimination of caspofungin, as a large percentage of the radiolabeled dose was recovered in urine and feces. Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 [N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine]. Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. These results suggest that distribution plays a prominent role in determining the plasma pharmacokinetics and disposition of caspofungin, as very little excretion or biotransformation occurred during the early days after dose administration, a period during which concentrations in plasma fell substantially. The disposition of caspofungin in preclinical species was similar to that reported previously in humans.

* Corresponding author. Mailing address: Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point, PA 19486. Phone: (215) 652-9308. Fax: (215) 652-2410. E-mail: punam_sandhu{at}merck.com.

{ddagger} Present address: Department of Drug Safety and Metabolism, Wyeth Pharmaceutical, Andover, MA 01810.

§ Present address: Department of Vaccine and Sterile Quality Operations, Merck Manufacturing Division, West Point, PA 19486.

Present address: Department of Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139.

{dagger} Deceased.

|| Present address: Department of Pharmacokinetics and Drug Metabolism, Amgen, Thousand Oaks, CA 91320.

Antimicrobial Agents and Chemotherapy, April 2004, p. 1272-1280, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1272-1280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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