Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma

Abstract

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 microCi) of [(3)H]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 [(3)H]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 (t(1/2) = 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 approximately 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.

FIG. 1.

Schematic of the compartmental model used in the distribution analysis. The elimination term (k₀) is from either compartment 1, 2, or 3, depending on the model used.

FIG. 2.

Mean plasma drug concentration profiles of caspofungin and total radioactivity following single 1-h i.v. adminitration of 70 mg of [³H]caspofungin to healthy male subjects. (A) Within-study comparisons of caspofungin and radioactivity profiles (expanded scale in inset plots). (B) Across-study comparison of radioactivity profile plotted on semi-log scale.

FIG. 3.

Mean distribution and excretion profiles of radioactivity following administration of a single 70-mg (200-μCi) dose of [³H]caspofungin to healthy male subjects (study A; n = 6).

FIG. 4.

Mean daily incremental recovery of radioactivity following administration of a single 70-mg (200-μCi) dose of [³H]caspofungin (study A; n = 6).

FIG. 5.

Fit of three-compartment linear model (clearance from central compartment) to individual plasma drug concentration profiles of caspofungin following administration of a single 70-mg (200-μCi) dose of [³H]caspofungin in study A (an expanded scale is shown in inset plots).

FIG. 6.

Time course of mean apparent volume of distribution of caspofungin following a single 70-mg dose of caspofungin as estimated by three-compartment linear modeling of plasma concentration-time data from study A (expanded scale is shown in the inset plot).