MICA: NTD Highlight Notice - Defining PK/PD relationships of anti-leishmanial drugs - a novel approach for anti-leishmanial drug development

利什曼病是由利什曼属寄生虫引起的一种被忽视的热带病。该病有多种形式，从局部和自愈的皮肤利什曼病（CL）到全身内脏利什曼病（VL），如果不治疗是致命的。全世界有1200多万人面临疾病风险，估计每年有5万人因VL死亡。目前没有疫苗，可用的药物也很少。所有的药物都有其局限性，如耐药、疗程长、毒性、给药方式和费用高。在人类中，利什曼原虫在巨噬细胞内存活和繁殖，而在VL病例中，巨噬细胞存在于肝脏、脾脏和骨髓中。对于有效的药物来说，理想情况下，它应该达到感染部位的浓度（药代动力学性质，PK），可以杀死寄生虫（药效学性质，PD），而不会对身体的其他部位产生毒性。良好给药方案的目的是在感染部位提供并保持有效的药物水平，以便在数天内成功杀死所有寄生虫。化学家设计一种新药的目的是赋予其特性，使其最大限度地分布到这些感染部位。因此，确定药物PKs和PDs之间的关系在药物开发和药物治疗中都很重要。目前，我们对用于治疗利什曼病的任何药物的PKs和pd知之甚少，对感染部位的药物作用和药物浓度一无所知。目前治疗中使用的给药方案尚未基于对PK - PD的理解进行优化，这可能会提高疗效，降低毒性，减少耐药机会；这同样适用于药物组合的设计。我们的目标是通过描述已建立的抗利什曼药物的PK/PD关系和提供预测模型来填补这一知识空白，这些模型可用于药物开发，由学术团体和制药行业，以及确定剂量方案和最佳药物组合。我们将确保将成功建立的方法和模型提供给学术界以及在这一领域有方案的制药和生物技术公司。我们打算为这一被忽视的热带病的新型和急需的治疗剂的更具成本效益和效率的开发作出贡献。

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. The disease has many forms, ranging from localized and self-healing cutaneous leishmaniasis (CL) to the systemic visceral leishmaniasis (VL), which is fatal if not treated. There are more than 12 million people at risk of disease worldwide and an estimated 50 000 deaths per year due to VL. There are no vaccines and there are few drugs available. All the drugs have limitations, for example, resistance, long treatment courses, toxicity, methods of administration and high cost. In humans the Leishmania parasites survive and multiply inside macrophage cells, which in case of VL are found in the liver, spleen and bone marrow. For a drug to be effective it should ideally reach a concentration at the site of infection (it's pharmacokinetic property, PK) which can kill the parasite (it's pharmacodynamic property, PD) without being toxic to other parts of the body. The aim of a good dosing regimen is to deliver and keep effective drug levels at the site of infection to successfully kill all the parasites over several days. The aim of the chemists designing a new drug is to give it the properties that maximise its distribution to these sites of infection. The determination of the relationship between drug PKs and PDs is therefore important in both drug development and drug treatment. Currently we know very little about the PKs and PDs of any of the drugs used for leishmaniasis and nothing about drug action and drug concentration at the site of infection. The dosing regimens used in treatments today have not been optimised based upon this PK PD understanding, which could lead to improved efficacy, lower toxicity, and less chance of resistance; the same applies to the design of drug combinations. We aim to fill this knowledge gap by characterising the PK/PD relationships of established anti-leishmanial drugs and provision of predictive models that can be used in both drug development, by academic groups and the pharmaceutical industry, and in determining dose regimens and the best drug combinations. We will ensure that the successfully established methods and models are made available to the academic community and pharmaceutical and biotechnology companies with programmes in this field. We intend to make a contribution to the more cost-effective and efficient development of novel and much-needed therapeutic agents for this neglected tropical disease.