The development of clinically effective drugs that could complement existing vaccines is urgently needed to reduce the morbidity and mortality associated with COVID-19. Drug-metabolizing enzymes, membrane-associated drug transporters, and inflammatory responses can partly determine the safety and efficacy of COVID-19 drugs by controlling their concentrations in both the systemic circulation and in peripheral tissues. It is still unknown how these factors affect how well COVID-19 drugs work in the clinic. We explore how drug metabolism and transport, as well as SARS-CoV-2-associated inflammatory response at disease target sites, may affect the clinical outcomes of COVID-19 drugs. In addition, we provide expert opinion on potential strategies for overcoming the clinical pharmacology and pathophysiological obstacles to improve COVID-19 drug effectiveness.