Carlo Patrono1. 1. Department of Pharmacology, Catholic University School of Medicine, Rome, Italy. Electronic address: carlo.patrono@rm.unicatt.it.
Abstract
PURPOSE: This review discusses the role of clinical pharmacology in the development of low-dose aspirin and other antiplatelet agents during the past 30 years, emphasizing the main determinants of several success stories as well as of complete failures in the field. METHODS: The author employs personal appraisal of the literature, with emphasis on personal contributions to the field. FINDINGS: Low-dose aspirin provides an interesting paradigm of the independent development of a "new" antiplatelet agent by the medical/scientific community. Aspirin "resistance," improved dosing regimens for personalized therapy, and chemoprevention of colorectal cancer are thoroughly discussed. The industry-driven development paradigm includes 12 mechanism-based antiplatelet agents. Of those completing Phase 3, only 6 have been approved for the acute treatment or secondary prevention of atherothrombosis. Inadequate Phase 2 studies were largely involved in Phase 3 failures. IMPLICATIONS: The design of mechanism-based pharmacodynamic biomarkers and sophisticated Phase 2 investigations appear as an important key to successful drug development in this field. Clinical pharmacology has an excellent track record in this endeavor, and its role needs to be expanded, as suggested by the case studies discussed in this review. Finally, the choice of appropriate platelet-dependent end points and homogeneous clinical settings for Phase 3 trials not only represent desirable objectives for an integrated scientific and regulatory discussion but also deserve proper ethical consideration by all stakeholders to avoid an unacceptable burden of drug toxicity and an unsustainable waste of financial resources.
PURPOSE: This review discusses the role of clinical pharmacology in the development of low-dose aspirin and other antiplatelet agents during the past 30 years, emphasizing the main determinants of several success stories as well as of complete failures in the field. METHODS: The author employs personal appraisal of the literature, with emphasis on personal contributions to the field. FINDINGS: Low-dose aspirin provides an interesting paradigm of the independent development of a "new" antiplatelet agent by the medical/scientific community. Aspirin "resistance," improved dosing regimens for personalized therapy, and chemoprevention of colorectal cancer are thoroughly discussed. The industry-driven development paradigm includes 12 mechanism-based antiplatelet agents. Of those completing Phase 3, only 6 have been approved for the acute treatment or secondary prevention of atherothrombosis. Inadequate Phase 2 studies were largely involved in Phase 3 failures. IMPLICATIONS: The design of mechanism-based pharmacodynamic biomarkers and sophisticated Phase 2 investigations appear as an important key to successful drug development in this field. Clinical pharmacology has an excellent track record in this endeavor, and its role needs to be expanded, as suggested by the case studies discussed in this review. Finally, the choice of appropriate platelet-dependent end points and homogeneous clinical settings for Phase 3 trials not only represent desirable objectives for an integrated scientific and regulatory discussion but also deserve proper ethical consideration by all stakeholders to avoid an unacceptable burden of drug toxicity and an unsustainable waste of financial resources.