Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Acta Pharmacol Sin. 2018 Sep;39(9):1533-1543. doi: 10.1038/aps.2017.176. Epub 2018 May 31.
Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.
卡泊芬净是一种棘白菌素类抗真菌药物，被批准为中重度疾病或近期接触唑类药物的侵袭性念珠菌病患者的一线治疗药物。本研究建立了一个基于全身生理学的药代动力学（WB-PBPK）模型，以预测卡泊芬净的药代动力学（PK），并结合蒙特卡罗模拟（MCS）优化不同类型患者卡泊芬净的临床剂量方案。利用来自 4 项普通患者、Child-Pugh B 级重症监护病房（ICU）患者、连续性肾脏替代治疗（CRRT）的 ICU 患者、轻度和中度肝不全（HI）患者的既往试验的原始数据，建立和验证了卡泊芬净的 WB-PBPK 模型。使用 MCS 优化这些患者的卡泊芬净临床剂量方案。累积反应分数（CFR）值≥90%被认为是实现最佳经验治疗的最低值。WB-PBPK 模型的模拟结果与所有试验的观察值吻合良好。对于卡泊芬净 70/50mg 的普通患者和 ICU 患者，AUC 和 Cmax 随体重（BW）的增加而降低，且变化较大。MCS 显示，所有普通患者无论 BW 如何，均可达到 CFR≥90%。但并非所有 BW 较高（≥70kg）的 ICU 患者都能达到 CFR≥90%。与普通患者的标准剂量方案相比，Child-Pugh B 级 ICU 患者给予卡泊芬净 70/35mg 可显著降低 AUC 和 Cmax，但在 Child-Pugh B 级中度 HI 患者中获得相似的 AUC 和 Cmax。卡泊芬净的 WB-PBPK 模型能够正确预测所有人群的 PK。结合 MCS 的 WB-PBPK 模型可成功优化所有患者人群的卡泊芬净临床剂量方案。
