Pharmacokinetics of caspofungin acetate to guide optimal dosing in cats

Abstract

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 (Cmax): 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 Cmax first dose was 14.8 μg/mL, Cmax at steady state was 19.8 μg/mL, Cmin was 5 μg/mL and Cmax: MEC was >20 in 42.6% of cats after multiple doses. An optimal Cmax: 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, Cmin 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 Cmin 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 Cmax: MEC window and provide consistent exposure between doses.

Invasive fungal infections and oomycoses in cats 2. Antifungal therapy

“…Caspofungin is the only echinocandin for which pharmacokinetic data are available in cats. 60 < Activity Echinocandins are fungicidal against Candida species, and fungistatic against Aspergillus, Penicillium and Purpureocillium species. 61 They have some activity against Sporothrix, Bipolaris, Scedosporium, Pseud allescheria and Fonsecaea species.…”

“…68 A pharmacokinetic study, in which caspofungin was administered to six cats for 7 days, reported transient fever in one cat and transient diarrhoea in another as the only AEs. 60 < Clinical use Caspofungin has been used to treat SoA in cats.…”

“… 11 , 38 Pharmacokinetic modeling data support the use of caspofungin in SOA, with effective target drug concentrations likely achieved when used as recommended in Table 1 . 60 The combination of caspofungin and PCZ has also been used to treat invasive aspergillosis in humans caused by the same agents as feline SOA (eg, Aspergillus udagawae). 88 Some feline cases have shown improvement with the addition of orbital exenteration or debridement of orbital granu-lomas to the treatment regimen; 42 , 89 overall, however, surgery has not been shown to improve outcomes compared with antifungal therapy alone.…”

News

“…5,6 • Determining the pharmacokinetics and pharmacodynamics of caspofungin in healthy cats, formed the basis of a Master's thesis and resulted in a presentation at an international conference and a publication. 7 This work was just one part of 6 years of research on canine and feline aspergillosis, with four prior publications from previous ACAHF funding.…”