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Antimicrobial Agents and Chemotherapy, March 2004, p. 815-823, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.815-823.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma

Julie A. Stone,1* Xin Xu,1 Gregory A. Winchell,1 Paul J. Deutsch,1 Paul G. Pearson,1 Elizabeth M. Migoya,1 Goutam C. Mistry,1 Liwen Xi,1 Alisha Miller,1 Punam Sandhu,1 Romi Singh,1 Florencia deLuna,1 Stacy C. Dilzer,2 and Kenneth C. Lasseter2

Merck Research Laboratories, West Point, Pennsylvania 19486,1 Clinical Pharmacology Associates, Miami, Florida 331422

Received 16 July 2003/ Returned for modification 3 October 2003/ Accepted 5 December 2003

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 µCi) of [3H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [3H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t1/2 = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ~92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.

* Corresponding author. Mailing address: WP75-100, Merck Research Laboratories, West Point, PA 19486. Phone: (215) 652-5705. Fax: (215) 993-3533. E-mail: julie_stone{at}merck.com.

Antimicrobial Agents and Chemotherapy, March 2004, p. 815-823, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.815-823.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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