ABSTRACT The Covid‐19 pandemic highlighted the urgent need for effective therapies against emerging pathogens. Drug repurposing, defined as the use of existing medications for new therapeutic purposes, was extensively pursued for SARS‐CoV‐2 but has not yielded successful treatments. This narrative review critically examines the pharmacological and methodological factors that contributed to these unsuccessful outcomes, paying particular attention to tests of azithromycin and hydroxychloroquine. There are many reasons the promise of repurposed drugs was not realized. Many repurposed compounds displayed promising in vitro antiviral activity that did not translate into clinical efficacy. Major pharmacokinetic (PK) limitations, for example, poor oral bioavailability, low concentrations in pulmonary tissue, and extensive plasma protein binding, prevented these drugs from reaching therapeutic levels in humans. Preclinical research often relied on non‐human cell lines and animal models that inadequately reflected human physiology, leading to misleading experimental outcomes. Clinical trials were often undermined by methodological limitations, including endpoints with uncertain clinical significance, suboptimal comparators, and insufficient attention paid to key PK and pharmacodynamic (PD) parameters such as half maximal effective concentration (EC50) values. This narrative review emphasizes the importance of integrating comprehensive PK/PD assessments, relevant experimental models, and rigorous trial design to strengthen drug development during future health crises. The relative success of antivirals including molnupiravir, nirmatrelvir, and remdesivir, which were either novel or previously unapproved compounds, suggests the value of designing and developing targeted antivirals. We must coordinate global research, develop pharmacologically sound strategies, and use evidence‐based decision‐making to effectively prepare for future pandemics and quickly produce effective treatments.
Ghezala et al. (Sun,) studied this question.