Pharmacological modelling and data analysis in decision support of antimalarial drug dosing regimens

对感染疟疾的个人进行成功的治疗意味着这种药物可以解决他们的症状，清除他们血液中的所有寄生虫，而不会产生伤害患者的副作用，或者让他们在未来使用这种药物时犹豫不决。在人群水平上的治疗成功意味着该药物是有效和安全的，建立了良好的声誉，优化了患者的依从性，减少了接受治疗的患者的疟疾传播，降低了出现新的抗药性突变的可能性，并减缓了任何现有抗药性寄生虫的传播速度。为了实现这些目标，需要一种清晰、明确的方法来设计和优化给药方案。治疗结果取决于一系列复杂的因素，包括患者如何处理药物的自然变异性(PK)、寄生虫对药物的敏感性(PD)以及患者药物摄入量的变化，取决于他们的体重、年龄或身高，以及患者的依从性。最近的发展导致了日益强大和准确的疟疾模拟模型，这使我们能够更准确地模拟药物治疗。随着这些模型的成熟，人们越来越认识到，结合不同数据来源的综合建模方法将有助于为新的和目前实施的抗疟疾药物开发最佳药物组合和剂量方案。我们一直在开发和完善抗疟疾药物治疗的模拟模型，作为大型疟疾模拟研究联盟OpenMalaria的合作伙伴之一，以使它们现在可以成功地捕捉到在现实生活中注意到的治疗结果的广泛变化模式。我们现在建议进一步改进和校准这一方法，并专门开发它们，将来自几个领域和临床来源的数据结合起来，以解决围绕最新一代抗疟疾药物青蒿素联合疗法(ACTS)部署的操作问题。我们拥有一个专家团队，他们拥有从建模、药理学、临床和抗疟疾药物政策知识在内的各种专业知识，以确保根据药物开发商和政策制定者的需求开发模型。

Successful treatment of an individual infected with malaria means that the drug resolves their symptoms and clears all parasites from their blood without causing side effects that harm the patient or make them hesitant to use the drug in the future. Treatment success at population level means that the drug is effective and safe, develops a good reputation that optimises patient compliance, reduces malaria transmission from treated patients, reduces the likelihood of new drug resistant mutations arising, and slows the rate of spread of any existing resistant parasites. A clear, explicit methodology is needed to design and optimise dosing regimens to achieve these aims.Treatment outcome rests on a complex variety of factors, including natural variability in how patients processes the drug (PK), variation in parasite sensitivity to the drug (PD) and variation in patient drug intake depending on their weight, age or height, and patient compliance. Recent developments have resulted in increasingly powerful and accurate simulation models for malaria which has allowed us to simulate drug treatment more accurately. As these models mature it is increasingly recognised that an integrated modelling method that combines different sources of data will help support the development of optimal drug combinations and dosing regimens for new and currently implemented antimalarial drugs.We have been developing and refining simulation models of antimalarial drug treatment as one of the partners of a large malaria modelling research consortium, OpenMalaria, to the state that they can now successfully capture the broad patterns of variation in treatment outcome noted in real-life. We now propose to further refine and calibrate this methodology, and specifically develop them to combine data from several field and clinical sources to address operational questions surrounding deployment of the latest generation of antimalarial drugs, the artemisinin-combination therapies (ACTs). We do this with a team of experts that range in expertise from modelling, pharmacology, clinical and policy knowledge on antimalarials to ensure that the models are developed according to the needs of drug developers and policy makers.