The healthcare business of Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
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Toxicol Appl Pharmacol. 2022 May 15;443:116006. doi: 10.1016/j.taap.2022.116006. Epub 2022 Mar 31.
M5717 is a novel drug inhibiting synthesis of elongation factor 2 (PeEF2) in Plasmodium species, showing potent anti-malarial activity in preclinical studies. Traditional daily-dosing animal experiments estimating maximum safe starting dose for a first-in-human study ('no observed adverse effect level'; NOAEL) were unsuccessful due to the long pharmacokinetic half-life of M5717, causing significant drug accumulation and high exposure. This study describes an innovative strategy to produce a GLP-certified toxicology package and estimate NOAEL for long-lasting molecules like M5717. Simulated pharmacokinetic/toxicokinetic profiles were used to design the dosing schedule for preclinical safety studies and to determine the 14-day total exposure. Animals (rats/dogs) were administered various doses of M5717 using an intermittent dosing schedule allowing partial drug elimination and alleviation of toxicity during off-treatment days to maintain a minimal parasitical concentration (MPC) of 10 ng/mL; subsequently animals were monitored for toxicity and mortality. Results showed good correlation to the modelled data used to design the dosing regimen and required MPC was reached for M5717 in study animals and could be used to calculate NOAEL. This fit-for-purpose study design allowed for maintaining clinically relevant exposure to M5717, whilst minimizing toxicity-causing compound accumulation, an aspect unaddressed by traditional NOAEL-estimating experiments. This is the first time that a compound-specific, species-specific, kinetic model-based approach to preclinical study design for regulatory toxicology studies has been described and applied to an antimalarial drug candidate with long pharmacokinetic half-life. It has potential for application to other drugs with long half-lives, supporting their clinical development.
M5717 是一种新型药物，可抑制疟原虫属中延伸因子 2（PeEF2）的合成，在临床前研究中表现出强大的抗疟活性。由于 M5717 的药代动力学半衰期较长，导致药物蓄积和暴露量高，传统的每日剂量动物实验来估计人体首次研究的最大安全起始剂量（“无观察到不良效应水平”；NOAEL）均不成功。本研究描述了一种创新策略，用于生成 GLP 认证的毒理学方案，并估计像 M5717 这样的长效分子的 NOAEL。模拟的药代动力学/毒代动力学曲线用于设计临床前安全性研究的给药方案，并确定 14 天的总暴露量。使用间歇性给药方案，使动物（大鼠/狗）接受各种剂量的 M5717，允许部分药物消除并在停药期间减轻毒性，以维持最小寄生虫浓度（MPC）为 10ng/mL；随后监测动物的毒性和死亡率。结果与用于设计给药方案的模型数据具有良好的相关性，并且研究动物中达到了 M5717 的 MPC，可用于计算 NOAEL。这种适合目的的研究设计允许维持与临床相关的 M5717 暴露，同时最大限度地减少毒性引起的化合物蓄积，这是传统的 NOAEL 估计实验未解决的问题。这是首次描述并应用于具有长药代动力学半衰期的抗疟候选药物的基于特定化合物、特定物种、基于动力学模型的临床前研究设计方法，具有应用于其他长半衰期药物的潜力，支持其临床开发。
