Department of Pharmacy, the First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou, 350005, People's Republic of China.
Eur J Clin Pharmacol. 2021 Jul;77(7):989-998. doi: 10.1007/s00228-020-03072-y. Epub 2021 Jan 15.
U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function.
The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI).
The fold error values of PK parameters (AUC, C, T) were all within 1.5. The telavancin AUC was predicted to increase 1.07-fold in mild RI, 1.23-fold in moderate RI, 1.41-fold in severe RI, and 1.57-fold in end-stage renal disease (ESRD), compared with that in obese HAP with normal renal function. The PBPK model combined with Monte Carlo simulations (MCS) suggested that dose adjustment based on a 750-mg-fixed dose could achieve effectiveness with reduced risk of toxicity, compared with current TBW-based dosing recommendations.
The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.
美国食品和药物管理局（FDA）推荐的替拉凡星剂量基于总体重（TBW），但缺乏针对肾功能不同的肥胖患者的调整方案。我们的目的是开发替拉凡星的生理基于药代动力学（PBPK）模型，为患有医院获得性肺炎（HAP）和不同肾功能的肥胖患者设计优化的给药方案。
使用不同肾功能的健康人群和肾功能正常的肥胖人群的替拉凡星临床药代动力学（PK）数据验证 PBPK 模型。然后，应用 PBPK 模型预测肾功能损害（RI）的肥胖 HAP 患者的 PK。
PK 参数（AUC、C、T）的折叠误差值均在 1.5 以内。与肾功能正常的肥胖 HAP 患者相比，轻度 RI、中度 RI、重度 RI 和终末期肾病（ESRD）患者的替拉凡星 AUC 预计分别增加 1.07 倍、1.23 倍、1.41 倍和 1.57 倍。PBPK 模型结合蒙特卡罗模拟（MCS）表明，与基于 TBW 的剂量推荐相比，基于 750mg 固定剂量的剂量调整可提高疗效并降低毒性风险。
PBPK 模拟表明，在肥胖合并 RI 的情况下，应避免使用基于 TBW 的方案。PBPK 模型对肥胖患者的剂量建议为：肾功能正常和轻度 RI 时每日 750mg，中度 RI 时每日 610mg，重度 RI 时每日 530mg，ESRD 时每日 480mg。
