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 Ci) 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 ϳ92% 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.Caspofungin (CANCIDAS; MK-0991) is a parenteral antifungal agent that inhibits 1,3-␤-D-glucan synthesis, which forms a critical component of many fungal cell walls (4). Caspofungin is active against many clinically important fungal species, including Candida spp. and Aspergillus spp. (3,5,7,14), and in clinical trials it has been shown to be efficacious in the treatment of esophageal candidiasis (1, 15, 16), invasive candidiasis (9), and invasive aspergillosis (J. Maertens, I. Raad, G. Petrikkos, et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-868, 2002). This paper describes results from two studies conducted in healthy human subjects to investigate the disposition of caspofungin following intravenous (i.v.) infusion of radiolabeled caspofungin and supportive studies of [ 3 H]caspofungin tissue distribution in rats, in vitro metabolism, and in vitro binding and partitioning in human plasma and blood. The metabolites of caspofungin, a cyclic hexapeptide, in humans have been previously reported (2). Caspofungin is the major component of radioactivity in plasma and urine in the first 24 to 30 h postdose, with a ring-opened form of caspofungin, M0, comprising a minor component. At time points of Ն5 days, M0 was the major component in plasma, and urine radioactivity was largely comprised of the synthetic amino acid dihydoxyhomotyrosine (M1) and its N-acetyl derivative (M2). Caspofungin...

Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study of Patients with Invasive Aspergillosis

“…The mechanism of PK nonlinearity is unclear; the ␥ phase, which becomes apparent at higher doses, might explain the extended time required to reach steady state at higher doses. Uptake of CAS from plasma into hepatocytes and possibly other tissue cells is the rate-determining step for plasma clearance of CAS: the hepatic uptake appears to be a slow process, likely mediated, at least in part, by an active OATP1B1-mediated transport process (28,32,33). There might be a slight saturation of this uptake at higher CAS doses.…”

“…There might be a slight saturation of this uptake at higher CAS doses. Stone et al (33) considered the small deviations from dose proportionality to be not clinically meaningful.…”

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“…In contrast, CSF concentrations are similar to those in the blood within 30 min of dosing (102). The administration of caspofungin to rodents results in brain tissue concentrations and exposures that are approximately 10% of those in plasma (103,104). In a single patient with CNS coccidioidomycosis, CSF concentrations of caspofungin were undetectable, despite concentrations in plasma of 2.7 to 5.5 g/ml (105).…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…Its plasma profile is determined primarily by its rate of distribution from plasma into tissues, rather than by metabolism or excretion. 95 Uptake occurs into hepatocytes via an initial rapid reversible adsorption to the cell surface and a second slow phase of transport across the cell membrane, 95,96 mediated by organic anion transporter protein 1B1 (OATP1B1). 96 Interactions with other transporters are detailed in Table 4.…”