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Abstract：
OBJECTIVE: 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.
METHODS: 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).
RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf 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.
CONCLUSIONS: 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.
METHODS: 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).
RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf 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.
CONCLUSIONS: 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.
摘要：
目的：美国食品和药物管理局（FDA）推荐的telavancin剂量是基于总体重（TBW），但缺乏针对肾功能不同的肥胖受试者的调整方案。我们的目标是开发一种基于生理的替拉万星药代动力学（PBPK）模型，以设计针对患有医院获得性肺炎（HAP）和肾功能变化的肥胖患者的优化给药方案。
方法：使用telavancin在肾功能不同的健康人群和肾功能正常的肥胖人群中的临床药代动力学（PK）数据验证了PBPK模型。然后，PBPK模型用于预测肥胖HAP合并肾损害(RI)患者的PK.
结果：PK参数的倍数误差值（AUC，Cmax,Tmax)均在1.5以内。预测telavancinAUC0-inf在轻度RI中增加1.07倍，中度RI的1.23倍，严重RI的1.41倍，和1.57倍的终末期肾病（ESRD），与肾功能正常的肥胖HAP相比。PBPK模型与蒙特卡罗模拟（MCS）相结合表明，基于750mg固定剂量的剂量调整可以在降低毒性风险的情况下实现有效性。与目前基于TBW的给药建议相比。
结论：PBPK模拟提出应避免使用基于TBW的方案治疗伴有RI的肥胖症。对于正常肾功能和轻度RI，PBPK模型中肥胖的剂量建议为每日750mg，中度RI每日610毫克，严重RI每日530毫克，ESRD每日480mg。
方法：使用telavancin在肾功能不同的健康人群和肾功能正常的肥胖人群中的临床药代动力学（PK）数据验证了PBPK模型。然后，PBPK模型用于预测肥胖HAP合并肾损害(RI)患者的PK.
结果：PK参数的倍数误差值（AUC，Cmax,Tmax)均在1.5以内。预测telavancinAUC0-inf在轻度RI中增加1.07倍，中度RI的1.23倍，严重RI的1.41倍，和1.57倍的终末期肾病（ESRD），与肾功能正常的肥胖HAP相比。PBPK模型与蒙特卡罗模拟（MCS）相结合表明，基于750mg固定剂量的剂量调整可以在降低毒性风险的情况下实现有效性。与目前基于TBW的给药建议相比。
结论：PBPK模拟提出应避免使用基于TBW的方案治疗伴有RI的肥胖症。对于正常肾功能和轻度RI，PBPK模型中肥胖的剂量建议为每日750mg，中度RI每日610毫克，严重RI每日530毫克，ESRD每日480mg。
