Pharmacokinetic considerations to optimize clinical outcomes for COVID-19 drugs

Abstract

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.

Keywords: COVID-19; SARS-CoV-2-associated inflammatory response; clinical pharmacology; drug-metabolizing enzymes; membrane-associated drug transporters; pharmacokinetics, pharmacodynamics.

Figure 1

Key figure. Interactions between human pulmonary drug clinical pharmacology and COVID-19 pathophysiology. (A) SARS-CoV-2 infects the human lung and elicits an immune response. The inflammatory response could alter the levels of clinically relevant drug-metabolizing enzymes and membrane-associated drug transporters in the lung. (B) Dysregulated pulmonary drug-metabolizing enzymes and membrane transporters could modify the concentration of COVID-19 drugs in the lungs leading to altered drug pharmacokinetic (PK) and pharmacodynamic (PD) profiles. For example, drug concentrations below the pulmonary therapeutic range would cause inefficacy whereas drug concentrations higher than the therapeutic range may result in toxicity. Other SARS-CoV-2 target sites, including the brain and testes, are expected to display similar interactions. Abbreviations: ED₅₀, 50% effective dose; TD₅₀, 50% toxicity dose.

Figure 2

Dysregulation of pulmonary drug pharmacokinetics by COVID-19-associated inflammatory response. (A) SARS-CoV-2 infection can cause severe inflammatory response with elevated proinflammatory cytokines such as IL-6, IL-1β, and TNF-α. (B) All these inflammatory effects can dysregulate drug metabolism and transport leading to altered pulmonary drug concentrations. Higher or lower pulmonary drug concentrations can lead to toxicity or inefficacy, respectively. Other SARS-CoV-2 target sites, including the brain and testes, are expected to display similar interactions.