Plasma concentrations of caspofungin decline in a polyphasic manner following single 1 hour IV infusions. A short b-phase occurs immediately postinfusion, followed by a b phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, g-phase, (half-life of 40-50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of [³H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.

Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L 747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [³H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L 747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of [³H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min.

Plasma concentrations of caspofungin in healthy men and women were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender.

Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70-mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly (see PRECAUTIONS, Geriatric Use).

Brand Name: Cancidas
Generic Name: Caspofungin Acetate

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