Leshinsky Jana, McLachlan Andrew, Foster David J R, Norris Ross, Barrs Vanessa R
Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, Camperdown, New South Wales, Australia.
Faculty of Pharmacy and Education and Research on Ageing, The University of Sydney, Camperdown, New South Wales, Australia.
PLoS One. 2017 Jun 2;12(6):e0178783. doi: 10.1371/journal.pone.0178783. eCollection 2017.
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.
猫是最常见的发生侵袭性真菌性鼻-鼻窦炎的哺乳动物，该病由烟曲霉属隐匿种引起，这些隐匿种对唑类耐药但对卡对卡泊芬净敏感。在本研究中，采用非线性混合效应药代动力学建模和模拟来研究卡泊芬净的药代动力学，并使用卡泊芬净最低有效浓度（MEC）探索猫的给药方案。在给予单次及连续7天每日静脉注射1mg/kg卡泊芬净后，使用高效液相色谱-串联质谱法（HPLC-MS/MS）测定健康猫的血浆浓度。在最终的药代动力学模型中，使用最佳的最大浓度（Cmax）：MEC比值为10-20来指导卡泊芬净的疗效。对有或无负荷剂量的给药方案（剂量0.25-2mg/kg和给药间隔6-72小时）进行了模拟。使用1mg/kg剂量时，首次给药的Cmax为14.8μg/mL，稳态时Cmax为19.8μg/mL，Cmin为5μg/mL，多次给药后42.6%的猫Cmax：MEC>20。在使用0.75mg/kg q 24h或1mg/kg q 72h的卡泊芬净模拟中实现了最佳的Cmax：MEC比值。然而，在1mg/kg q 72h时，超过95%的群体Cmin<MEC（<1μg/mL）。使用1mg/kg的负荷剂量，随后每日剂量为0.75mg/kg，Cmax：MEC最佳，98%的群体Cmin>2.5μg/mL。基于建模数据，该给药方案可能达到目标治疗浓度，满足建议的Cmax：MEC范围，并在各剂量之间提供一致的暴露。
