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Antimicrobial Agents and Chemotherapy, November 2004, p. 4306-4314, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4306-4314.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Potential for Interactions between Caspofungin and Nelfinavir or Rifampin

Julie A. Stone,1* Elizabeth M. Migoya,1 Lisa Hickey,1 Gregory A. Winchell,1 Paul J. Deutsch,1 Kalyan Ghosh,1 Amanda Freeman,1 Sheng Bi,1 Rajesh Desai,1 Stacy C. Dilzer,2 Kenneth C. Lasseter,2 Walter K. Kraft,3 Howard Greenberg,3 and Scott A. Waldman3

Merck Research Laboratories, West Point,1 Thomas Jefferson University, Philadelphia, Pennsylvania,3 Clinical Pharmacology Associates, Miami, Florida2

Received 9 January 2004/ Returned for modification 14 March 2004/ Accepted 22 July 2004

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC0-24] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C24h), consistent with a net induction effect at steady state. Both the AUC and the C24h were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC0-24 on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C24h at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.

* Correspondence 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, November 2004, p. 4306-4314, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4306-4314.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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