Merck Research Laboratories, PO Box 2000, RY34-A500, Rahway, NJ, USA.
J Clin Pharmacol. 2011 Feb;51(2):202-11. doi: 10.1177/0091270010374853. Epub 2010 Aug 2.
Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.
卡泊芬净是首个新型抗真菌药物（棘白菌素类），适用于治疗原发性和复发性真菌感染。对于卡泊芬净或其他抗真菌治疗失败的患者，较高剂量的卡泊芬净可能是另一种选择。本研究评估了 16 名健康受试者单次接受 150 毫克和 210 毫克剂量，以及 20 名健康受试者连续 21 天每天接受 100 毫克剂量的卡泊芬净的安全性、耐受性和药代动力学。除了输注部位反应和 1 例丙氨酸氨基转移酶升高（≥2×和<4×正常值上限）外，卡泊芬净总体上耐受性良好。单次 150 毫克和 210 毫克剂量后的几何平均 AUC（0-∞）分别为 279.7 和 374.9µg·h/mL；峰浓度分别为 29.4 和 33.5µg/mL；24 小时后浓度分别为 2.8 和 4.2µg/mL。在第三周给药时达到稳态。多次给予 100 毫克剂量的卡泊芬净后，第 21 天的几何平均 AUC（0-24）为 227.4µg·h/mL，峰浓度为 20.9µg/mL，谷浓度为 4.7µg/mL。β 相 t(1/2)约为 8 至 13 小时。这些较高剂量的卡泊芬净药代动力学与较低剂量观察到的情况呈剂量比例，表明剂量增加时的蓄积呈适度非线性，这被认为无临床意义。
