J Infect Dis. 2014 Jul 1;210(1):146-53. doi: 10.1093/infdis/jiu039. Epub 2014 Jan 16.
Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL.
Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure.
The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure.
Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.
最近的报告表明，在印度次大陆，米替福新治疗内脏利什曼病（VL）的失败率很高。为了进一步探讨与这些治疗失败相关的药理学因素，对尼泊尔 VL 患者进行了一项群体药代动力学-药效学研究，以检查米替福新药物暴露与治疗失败之间的关系。
采用液相色谱串联质谱法分析治疗结束时米替福新的稳态血药浓度。采用非线性混合效应模型和逻辑回归模型进行群体药代动力学-药效学分析。探索米替福新暴露的个体估计值与治疗失败的关系。
总的治疗失败概率为 21%。血药浓度>米替福新半数最大有效浓度 10 倍的时间（中位数为 30.2 天）与治疗失败显著相关：米替福新暴露每减少 1 天，治疗失败的几率增加 1.08 倍（95%置信区间为 1.01-1.17）。
实现米替福新的充分暴露是 VL 治疗成功的一个重要且关键的因素，这表明迫切需要评估最近提出的最佳比例米替福新给药方案。本研究确立了米替福新治疗 VL 的药物暴露-效应关系的首个证据。
