Pharmacokinetics of caspofungin acetate to guide optimal dosing in cats

Cats are the most common mammal to develop invasive fungal rhinosinusitis caused by cryptic species in Aspergillus section Fumigati that are resistant to azoles but susceptible to caspofungin. In this study nonlinear mixed-effects pharmacokinetic modeling and simulation was used to investigate caspofungin pharmacokinetics and explore dosing regimens in cats using caspofungin minimum effective concentrations (MECs). Plasma concentrations in healthy cats were determined using HPLC-MS/MS after administration of a single and seven consecutive daily intravenous doses of 1 mg/kg caspofungin. In the final pharmacokinetic model an optimum maximum concentration (C(max)): MEC ratio of 10–20 was used to guide caspofungin efficacy. Simulations were performed for dosing regimens (doses 0.25–2 mg/kg and 6–72 h dosing intervals) with and without inclusion of a loading dose. Using a 1 mg/kg dose C(max) first dose was 14.8 μg/mL, C(max) at steady state was 19.8 μg/mL, C(min) was 5 μg/mL and C(max): MEC was >20 in 42.6% of cats after multiple doses. An optimal C(max): MEC ratio was achieved in caspofungin simulations using 0.75 mg/kg q 24 h or 1 mg/kg q 72h. However, at 1 mg/kg q 72h, C(min) was < MEC (<1 μg/mL) in over 95% of the population. Using a loading dose of 1 mg/kg and a daily dose of 0.75 mg/kg thereafter, the Cmax: MEC was optimal and C(min) was > 2.5 μg/mL for 98% of the population. Based on the modeling data this dosing regimen is likely to achieve target therapeutic concentrations, meet the proposed C(max): MEC window and provide consistent exposure between doses.