Pharmacometric optimization of second line drugs for MDR tuberculosis treatment

 描述(由申请人提供)：这项建议回应了开发疾病反应的强大生物标志物的研究需要，以及更好地了解当前结核病治疗方式的需要。耐多药结核病(MDR-TB)已被宣布为全球紧急情况。由于二线抗结核药物的毒性和有限的疗效，治疗结果很差。虽然有证据表明，关键药物的抗结核活性和大部分毒性都与药物暴露有关，但耐多药结核病患者的药代动力学/药效学(PK/PD)关系尚不清楚。在一组南非耐多药结核病患者中，我们计划：1)使用创新的药物计量学分析，以连续痰样本的液体培养阳性时间为基础，开发疾病回归的生物标记物模型；2)在非线性混合效应模型中描述构成标准治疗方案的五种药物的群体药代动力学；3)描述结核分枝杆菌分离株对这些药物的个体敏感性，以及人群中最低抑菌药物浓度的分布；4)确定与药物相关的副作用的频率；5)使用计算分析来量化联合使用的抗结核药物对疗效和毒性的个体贡献。我们建议使用结核的体外中空纤维模型(HFM-TB)来确定抗结核活性和抑制耐药性的药代动力学靶点。因此，在对数生长期、半休眠状态和胞内结核分枝杆菌中，将研究与最佳疗效、预防ADR和协同作用相关的(PK/PD)参数，并将其转化为患者。临床研究中定义的关键PK/PD关系也将在HFM-TB中进行调查。我们的研究将确定治疗耐多药结核病的剂量和药物组合，这些剂量和药物组合可能比目前使用的方案更有效，毒性更低。此外，疾病反应的生物标记物模型和计算分析方法的发展将使未来的治疗方案能够更有效地优化。

 DESCRIPTION (provided by applicant): This proposal responds to the research need to develop powerful biomarkers of disease response and the need to better understand current modalities of tuberculosis treatment. Multidrug-resistant tuberculosis (MDR-TB) has been declared a global emergency. Treatment outcomes are poor, driven by toxicity and limited efficacy of the 2nd-line antituberculosis drugs. Although there is evidence that both antituberculosis activity and most of the toxicity of the key drugs are related to drug exposure, the pharmacokinetic/pharmacodynamic (PK/PD) relationships in patients with MDR-TB are poorly characterized. In a cohort of South African patients with MDR-TB, we plan to: 1) use innovative pharmacometric analyses to develop a biomarker model of disease regression based on time-to-positivity in liquid culture of serial sputum samples; 2) describe the population pharmacokinetics of the five drugs constituting the standard treatment regimen in nonlinear mixed effects models; 3) describe the individual susceptibility of Mycobacterium tuberculosis isolates to those drugs, and the distribution to of the minimum inhibitory drug concentrations in the population; 4) define the frequency of drug-related side effects; 5) use computational analyses to quantify the individual contributions to efficacy and toxicity of the antituberculosis drugs used in combination. We propose to use in vitro hollow fiber models of tuberculosis (HFM-TB) to determine pharmacokinetic targets for antituberculosis activity and the suppression of resistance. Thus the (PK/PD) parameters associated with optimal efficacy, prevention of ADR and synergy will be investigated for moxifloxacin, pyrazinamide and kanamycin combinations in log-phase growth, semi-dormant and intracellular Mycobacterium tuberculosis, and then translated to patients using Monte Carlo simulations. The key PK/PD relationships defined in the clinical study will also be investigated in HFM-TB. Our study will identify doses and drug combinations for the treatment of MDR-TB that are likely to be more efficacious and less toxic than the currently used regimen. Moreover the development of a biomarker model of disease response and computational analytical methodologies will enable more efficient optimization of future regimens.