Service Pharmaceutique, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France.
UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, Université Lyon 1, Villeurbanne, France.
Clin Pharmacokinet. 2022 Oct;61(10):1443-1456. doi: 10.1007/s40262-022-01168-5. Epub 2022 Aug 16.
Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue.
A PBPK model of daptomycin was built using PK-Sim. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments.
The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy.
We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.
达托霉素已被推荐用于治疗骨和关节感染。先前的研究表明，达托霉素的批准剂量可能不足以使骨和关节感染患者达到最佳暴露水平。然而，这些研究假设骨暴露与稳态时达托霉素游离血浆浓度相似。我们试图建立达托霉素的生理基于药代动力学（PBPK）模型，以描述达托霉素在骨和皮肤组织中的分布动力学。
使用 PK-Sim 建立达托霉素的 PBPK 模型。从三项先前发表的研究中获得血浆和骨中的达托霉素浓度。使用药物理化特性、质量平衡、人体测量学和实验数据来构建和优化 PBPK 模型。使用常规诊断图对内源性验证 PBPK 模型。然后，使用 6、8、10 和 12 mg/kg/24 h 的剂量运行模拟。在 1000 名受试者中模拟药代动力学谱，并计算血液、皮肤和骨骼部位细菌最低抑菌浓度下浓度-时间曲线下面积的达标概率。
最终模型对所有数据集具有良好的拟合度，血液、皮肤和骨骼组织中所有药代动力学参数的绝对平均折叠误差在 0.5 到 2 之间。剂量模拟结果表明，金黄色葡萄球菌引起的菌血症（最低抑菌浓度>0.5 mg/L）或粪肠球菌引起的菌血症（最低抑菌浓度>1 mg/L）时，应使用≥10 mg/kg 的剂量；而骨和关节感染或复杂皮肤感染时，应使用≥12 mg/kg 的剂量。当考虑较低的最低抑菌浓度时，6-8 mg/kg 的剂量可能会有足够的成功率。然而，对于最低抑菌浓度>2 mg/L 的粪肠球菌引起的感染，需要更高的剂量和联合治疗才能最大限度地提高疗效。
我们开发了第一个用于骨和关节感染的达托霉素 PBPK/药效学模型，该模型证实需要更高的达托霉素剂量来优化骨组织中的暴露。然而，这种更高的剂量会引起安全性问题。在这种情况下，治疗药物监测和基于模型的精准给药似乎是必要的，以确保在个体基础上获得正确的暴露。
