Kristoffersson Anders N, David-Pierson Pascale, Parrott Neil J, Kuhlmann Olaf, Lave Thierry, Friberg Lena E, Nielsen Elisabet I
Department of Pharmaceutical Biosciences, Uppsala Universitet, Box 591, Uppsala, SE-751 24, Sweden.
F. Hoffmann-La Roche Ltd., Innovation Center Basel, Pharmaceuticals Sciences, Basel, Switzerland.
Pharm Res. 2016 May;33(5):1115-25. doi: 10.1007/s11095-016-1856-x. Epub 2016 Jan 19.
Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.
A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.
The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2.
A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.
基于药代动力学/药效学（PK/PD）指标的抗生素剂量预测依赖于该指标类型和大小对药代动力学（PK）、给药方案及细菌敏感性不敏感。在本研究中，我们进行模拟以验证针对美罗培南和铜绿假单胞菌的这些假设。
在计算机上复制一项已发表的小鼠剂量分割研究。评估PK/PD指标对实验设计、药物敏感性、最低抑菌浓度（MIC）不确定性及不同PK曲线的敏感性。
以fT＞MIC作为最佳预测指标时，先前小鼠研究数据得到很好的复制。然而，对于增加给药频率的情况，发现fAUC/MIC更具预测性，且该指标大小对药物敏感性敏感。对于人类PK，fT＞MIC和fAUC/MIC具有相似的预测能力，t1/2短时倾向于fT＞MIC，t1/2长时倾向于fAUC/MIC。
基于体外数据的纵向PKPD模型成功预测了先前美罗培南的体内研究。PK/PD指标的类型和大小对实验设计、MIC及PK敏感。因此，基于整合的PK-PKPD模型进行剂量选择模拟可能比使用固定的PK/PD指标目标更可取。
