title: Potential for interactions between caspofungin and nelfinavir or rifampin.
abstract: 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 [AUC(0-24)] 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 (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24h) 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 AUC(0-24) 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 C(24h) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA. julie_stone@merck.com
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stone
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Migoya
authors.forename: Lisa
authors.initials: L
authors.lastname: Hickey
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Winchell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Deutsch
authors.forename: Kalyan
authors.initials: K
authors.lastname: Ghosh
authors.forename: Amanda
authors.initials: A
authors.lastname: Freeman
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
authors.forename: Rajesh
authors.initials: R
authors.lastname: Desai
authors.forename: Stacy C
authors.initials: SC
authors.lastname: Dilzer
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.forename: Howard
authors.initials: H
authors.lastname: Greenberg
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000328:Adult; D000465:Algorithms; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077336:Caspofungin; D004338:Drug Combinations; D004347:Drug Interactions; D054714:Echinocandins; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D016014:Linear Models; D055666:Lipopeptides; D008297:Male; D019888:Nelfinavir / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000904:Antibiotics, Antitubercular; D000935:Antifungal Agents; D004338:Drug Combinations; D054714:Echinocandins; D017320:HIV Protease Inhibitors; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000077336:Caspofungin; D019888:Nelfinavir; D012293:Rifampin