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.

FIG. 1.

Schematic of compartmental model to describe the effect of rifampin on caspofungin pharmacokinetics.

FIG. 2.

Caspofungin plasma profiles following administration of caspofungin alone (50 mg administered IV once daily) or coadministration of caspofungin (as described above) and nelfinavir (1,250 mg administered orally twice daily) to healthy male subjects. Means and standard deviations (error bars) are indicated. Conc., concentration.

FIG. 3.

Caspofungin plasma profiles following administration of caspofungin alone (50 mg administered IV once daily) or coadministration of caspofungin (as described above) and rifampin (600 mg administered orally once daily) when both drugs were initiated on the same study day (study A). Means and standard deviations (error bars) are indicated. Conc., concentration.

FIG. 4.

Caspofungin plasma profiles following administration of caspofungin alone (50 mg administered IV once daily) or coadministration of caspofingin (as described above) and rifampin (600 mg administered orally once daily) when rifampin was initiated alone 14 days prior to coadministration with caspofungin (study B). Means and standard deviations (error bars) are indicated. Conc., concentration.

FIG. 5.

Caspofungin trough concentrations following administration of caspofungin alone (50 mg administered IV once daily) or coadministration of caspofungin (as described above) and rifampin (600 mg administered orally once daily). Means and standard deviations (error bars) are indicated. Conc., concentration.

FIG. 6.

Rifampin plasma profiles following administration of rifampin alone (600 mg administered orally once daily) or coadministration of rifampin (as described above) and caspofungin (50 mg administered IV once daily) (n = 14). Data are means. Conc., concentration.

FIG. 7.

Mean model fit to caspofungin concentration data from day 1 of coadministration in study A (caspofungin and rifampin initiated on same day) and from day 14 of coadministration in study B (pretreatment with rifampin alone). Conc., concentration.