Addressing Today’s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of theSMN2mRNA Splicing Modifier Risdiplam
| العنوان: | Addressing Today’s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of theSMN2mRNA Splicing Modifier Risdiplam |
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| المؤلفون: | Agnès Poirier, Heidemarie Kletzl, Cordula Stillhart, Stephen Fowler, Kenichi Umehara, Andreas Guenther, Andreas Brink, Nicole A. Kratochwil, Dietrich Tuerck, Christophe Husser, Mark Savage, Mohammed Ullah, Lutz Mueller, Yumi Cleary, Katja Heinig |
| المصدر: | Drug Metabolism and Disposition. 50:65-75 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pharmacology, Drug, Chemistry, In silico, media_common.quotation_subject, Pharmaceutical Science, Computational biology, Small molecule, Drug development, Pharmacokinetics, In vivo, Distribution (pharmacology), ADME, media_common |
| الوصف: | Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro - in vivo - in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development. Risdiplam (EVRYSDI®) - an orally bioavailable, small molecule approved by the U.S. Food and Drug Administration and more recently by the European Medicines Agency for the treatment of patients {greater than or equal to}2 months of age with spinal muscular atrophy (SMA), is presented here as a case study. Risdiplam is a low turnover compound whose metabolism is mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges of risdiplam are discussed: predicting in vivo hepatic clearance, determining in vitro metabolites with regard to metabolites in safety testing guidelines, elucidating enzymes responsible for clearance, and estimating potential drug-drug interactions. A combination of in vitro and in vivo results was successfully extrapolated and used to develop a robust physiologically based pharmacokinetic model of risdiplam. These results were verified through early clinical studies, further strengthening the understanding of the ADME properties of risdiplam in humans. These approaches can be applied to other compounds with similar ADME profiles, which may be difficult to investigate using standard methods. Significance Statement Risdiplam is the first approved, small molecule, survival of motor neuron 2 mRNA splicing modifier for the treatment of spinal muscular atrophy. The approach taken to characterize the absorption, distribution, metabolism and excretion (ADME) properties of risdiplam during clinical development incorporated in vitro-in vivo-in silico techniques, which may be applicable to other small molecules with challenging ADME. These strategies may be useful in improving the speed at which future drug molecules can be developed. |
| تدمد: | 1521-009X 0090-9556 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::a42eb9cb10d47b49d0cb86fb0a1206acTest https://doi.org/10.1124/dmd.121.000563Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi...........a42eb9cb10d47b49d0cb86fb0a1206ac |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1521009X 00909556 |
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