Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers.

Autor: Ahmed MA; Quantitative Clinical Pharmacology, Takeda Development Center, Cambridge, Massachusetts, USA., Krishna R; Certara Drug Development Solutions, Certara USA, Inc., Princeton, New Jersey, USA., Rayad N; Parexel International (MA) Corporation, Mississauga, ON, Canada.; Present address: Clinical Pharmacology and Safety Sciences, Alexion, AstraZeneca Rare Disease, Mississauga, ON, Canada., Albusaysi S; Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Mitra A; Clinical Pharmacology, Kura Oncology Inc, Boston, Massachusetts, USA., Shang E; Global Regulatory Affairs and Clinical Safety, Merck &Co., Inc., Rahway, New Jersey, USA., Hon YY; Divsion of Rare Diseases and Medical Genetics, Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, US Food and Drug Administration, Silver Spring, Maryland, USA., AbuAsal B; Division of Translational and Precision Medicine, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland, USA., Bakhaidar R; Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Roman YM; Division of Translational and Precision Medicine, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland, USA., Bhattacharya I; Quantitative Clinical Pharmacology, Takeda Development Center, Cambridge, Massachusetts, USA., Cloyd J; Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA., Patel M; Quantitative Clinical Pharmacology, Takeda Development Center, Cambridge, Massachusetts, USA., Kartha RV; Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA., Younis IR; Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Rahway, New Jersey, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 Dec; Vol. 116 (6), pp. 1412-1432. Date of Electronic Publication: 2024 Aug 16.
DOI: 10.1002/cpt.3407
Abstrakt: In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.
(© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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