Purpose

This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose.

Methods

We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration–time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated.

Results

In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05–0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20–60 mL/min and aged 65–95 years were calculated as 200–500 mg q24h.

Conclusion

These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

中文翻译：

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基于未结合达托霉素浓度和胱抑素C的非肥胖老年低白蛋白血症慢性肾病患者群体药代动力学分析及剂量优化

目的

本研究使用胱抑素 C (eGFRcys) 估计的肾小球滤过率评估了达托霉素在患有低白蛋白血症和慢性肾病 (CKD) 的非肥胖老年患者中的群体药代动力学，并估计了其最佳剂量。

方法

我们对未结合浓度的达托霉素进行了群体药代动力学分析。随机模拟了在稳态/最小抑菌浓度比≥66.6 时达到未结合达托霉素浓度-时间曲线下面积的 90% 目标概率。

结果

在 25 名≥65 岁患者的群体药代动力学分析中，使用 eGFRcys 和年龄作为未结合达托霉素中央区室清除协变量的二区室模型是最佳的。未结合的馏分率 (fu) 为 0.05–0.14。根据蒙特卡罗模拟，eGFRcys 为 20-60 mL/min 和 65-95 岁患者的最佳剂量计算为 200-500 mg q24h。

结论

这些结果表明，使用总浓度确定剂量可能会导致由 fu 的变化引起的低估或高估。患有低白蛋白血症和 CKD 的非肥胖老年患者的最佳剂量取决于 eGFRcys 和年龄，某些患者的标准剂量可能不够。