Caspofungin Acetate: An Antifungal Agent

Caspofungin Acetate: An Antifungal Agent

from American Journal of Health-System Pharmacy

Bioavailability and Pharmacokinetics

Stone and colleagues [26] studied the pharmacokinetics of caspofungin acetate in 12 healthy male subjects involved in three Phase I trials. In the first dose-ranging study, subjects were given single doses of caspofungin acetate ranging from 5 to 100 mg. Following a one-hour infusion, plasma levels of caspofungin acetate were found to increase proportionately as the dose increased to 100 mg. Across all dose ranges, the average plasma clearance and elimination half-life were 11 mL/min and 9 to 10 hours, respectively. An additional elimination phase and extended half-life were observed at higher doses.

The pharmacokinetics of multiple doses were evaluated in the second Phase I study that enrolled healthy male subjects (n = 5 or 6) randomized to receive daily infusions of 15, 35, and 70 mg of caspofungin acetate for 14 days.[26] All doses were infused over one hour. Between day 1 and day 14, a greater degree of drug accumulation was observed with the higher doses, such that the average accumulation was 25% at 15 mg/day, 34% at 35 mg/day, and 50% at 70 mg/day. Mean trough concentrations were 1.36 ± 0.3 mg/L on day 1 and 2.66 ± 0.55 mg/L on day 14 (Table 3).

In a third multiple-dose Phase I study, 10 subjects were given 70 mg of caspofungin acetate daily for 21 days.[26] The average accumulation was 39% on day 14 and 47% on day 21. As was the case with the previous multiple-dose study, serum levels of caspofungin acetate were consistently maintained above 1 mg/L throughout the 24-hour dosing period (Table 3).

In a single-dose study, caspofungin acetate was evaluated in 12 healthy elderly subjects (over age 64 years) and with pooled data from 12 healthy young controls (age 24 to 44 years).[27] All subjects were given a 70- mg dose of caspofungin acetate. Elderly subjects had a minimum creatinine clearance of 60 mL/min, and half of the participants were women. The geometric mean area under the curve (AUC) ratio for elderly subjects relative to young controls was 1.28. Geometric mean 24-hour concentration increased by 32%, and harmonic mean half-life lengthened by 26% in the elderly. As was the case with previous investigators,[28] no significant gender effects were observed. Although there was a modest effect of advanced age on pharmacokinetics, the authors concluded that the effect was not significant enough to warrant a dosage adjustment in elderly patients.

In a placebo-controlled Phase I study, the authors concluded that caspofungin acetate is not subject to drug interactions based on CYP3A4 inhibition.[28]

Hajdu and colleagues [29] investigated tissue penetration of caspofungin acetate in a murine model. Following intraperitoneal administration, tissue concentrations were measured as the AUC and compared with plasma concentrations. The highest concentrations were found in the following organs: liver (16 times plasma), kidneys (3 times), and large intestine (2 times). The organs with the lowest concentrations were the heart (0.3 times plasma), thigh (0.2 times), and brain (0.06 times). Caspofungin acetate distribution into red blood cells is minimal.

In vitro protein binding in animal and human sera is reported to be 80- 96%.[29,30] The exact route of elimination has not been determined, although the proposed route of elimination is hepatic, and less than 3% of the dose is eliminated unchanged in the urine.[29]

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