Computational pharmacology of rifampin in mice: an application to dose optimization with conflicting objectives in tuberculosis treatment.
Computational pharmacology of rifampin in mice: an application to dose optimization with conflicting objectives in tuberculosis treatment.
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DOI：
10.1007/s10928-014-9380-2
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发表时间：
2014-12
影响因子：
2.5
通讯作者：
Lyons MA
中科院分区：
文献类型：
--
作者：
Lyons MA
利福平在活动性肺结核(TB)治疗中的剂量选择说明了多药疗法中剂量优化的一些挑战。以利福平为基础的抗结核方案通常与抗逆转录病毒疗法相结合，以治疗人类免疫缺陷病毒(HIV)合并感染。利福平强大的细胞色素P450(CYP)酶诱导特性会引起显著的药物-药物相互作用，通过限制剂量来最小化药物相互作用，而通过增加剂量来最大限度地杀灭细菌。这种多重和相互冲突的目标导致了一组用于剂量优化的权衡最优解决方案，而不是单一的最佳解决方案。在这里，我们将药代动力学/药效学(PK/PD)建模与多目标优化相结合，以结核病感染小鼠为例，定量探索最佳剂量利福平治疗和不良反应之间的权衡。PK/PD模型描述了口服利福平后血浆和肝脏中利福平的浓度，以及肝脏CYP酶诱导和细菌杀灭动力学。我们包括描述抗菌效果的优化目标，CYP介导的药物-药物相互作用，以及药物暴露依赖的毒性。结果显示，非常规给药方案允许相对于均匀剂量提高疗效，而不增加药物-药物相互作用。此外，我们发现目前使用的利福平剂量在有效性和毒性之间的权衡方面几乎是最佳的。虽然受到PK/PD模型精度和适用性的限制，但这些结果为复杂剂量优化问题的实验研究提供了一条途径。这种方法可以扩展到包括额外的药物和优化目标，并可能为个体化用药提供有用的工具。
Dose selection for rifampin in the treatment of active pulmonary tuberculosis (TB) illustrates some of the challenges for dose optimization within multidrug therapies. Rifampin-based anti-TB regimens are often combined with antiretroviral therapies to treat human immunodeficiency virus (HIV) coinfection. The potent cytochrome P450 (CYP) enzyme inducing properties of rifampin give rise to significant drug-drug interactions, the minimization of which by limiting the dose, conflicts with the maximization of bacterial killing by increasing the dose. Such multiple and conflicting objectives lead to a set of trade-off optimal solutions for dose optimization rather than a single best solution. Here, we combine pharmacokinetic/pharmacodynamic (PK/PD) modeling with multiobjective optimization to quantitatively explore trade-offs between therapeutic and adverse effects of optimal dosing for the example of rifampin in TB-infected mice. The PK/PD model describes rifampin concentrations in plasma and liver following oral administration together with hepatic CYP enzyme induction and bacterial killing kinetics. We include optimization objectives descriptive of antimicrobial efficacy, CYP-mediated drug-drug interactions, and drug exposure-dependent toxicity. Results show non-conventional dosing scenarios that allow for increased efficacy relative to uniform dosing without increasing drug-drug interactions. Additionally, we find currently employed dosages for rifampin to be nearly optimal with respect to tradeoffs between efficacy and toxicity. While limited by the accuracy and applicability of the PK/PD model, these results provide an avenue for experimental investigation of complex dose optimization problems. This method can be extended to include additional drugs and optimization objectives, and may provide a useful tool for individualized medicine.