Prescribing in COVID‐19 patients: Should we take into account inflammation?

Many scientists and clinical pharmacologists have advocated for the right choice and combinations of repurposed drugs with which to treat patients in COVID-19, based on sound knowledge of clinical pharmacology, physiology and clinical therapeutics. ASCEPT-BPS subsequently highlighted the importance of applying core pharmacology principles at all stages of research to help identify the right dose of repurposed therapies, the right patient and the right treatment protocol. One of the recommendations was that there should be a thorough assessment of safety end-points in all trials, including those due to drug-drug and drug-disease interactions to ensure that there is a complete profile of the hazards of the medicine in relation to the benefits at different stages of the disease. We wish to comment further on this important point in relation to the impact of inflammation on drug disposition and drug-drug interactions (DDIs). The systemic inflammatory response to SARS-CoV-2 results in the release of cytokines in symptomatic COVID-19 patients. Subsequently, intracellular signalling cascades are activated, leading to the downregulation of cytochrome P450 enzymes (CYP), particularly CYP3A4. These findings are in line with the reported strikingly elevated concentrations of the boosted CYP3A4 substrate lopinavir (LPV) and are supported by clinical observations showing a correlation between elevated Creactive protein (CRP) values and high plasma concentrations of LPV/r. Inflammatory cytokines also impact drug transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) leading to increased absorption of substrate drugs. Several drugs repurposed for the treatment of COVID-19 undergo varying degrees of CYP3A4-mediated metabolism (i.e., lopinavir/ritonavir (LPV/r), atazanavir, chloroquine, hydroxychloroquine, dexamethasone, and ruxolitinib) consequently their exposure may be increased in COVID-19 patients with significant systemic inflammatory response. Elevated drug concentrations may increase the risk of adverse drug effects and accentuate the magnitude of DDIs with comedications whose metabolism is inhibited by LPV/r. The effect of inflammation on dexamethasone is more difficult to predict. Dexamethasone has been used at a dose of 6 mg once daily up to 10 days in the RECOVERY trial. Dexamethasone is known to be a weak (low dose) to moderate (high dose) inducer of CYP3A4. In the context of inflammation, dexamethasone exposure is expected to increase initially thereby increasing the inducing effect (i.e., going from a weak inducing effect as expected with a 6 mg dose to a moderate inducing effect due to the predicted initial twofold to threefold increase in dexamethasone exposure). The moderate inducing effect of dexamethasone together with the decrease in inhibitory cytokines is expected to reverse the initial inhibitory effect of inflammation on CYP3A4 leading to an overall inducing effect over the treatment course. Finally, data indicate that hydroxychloroquine plasma concentrations are not elevated in COVID-19 patients unlike LPV, and this may reflect the involvement of multiple metabolic pathways. Since hydroxychloroquine accumulates highly in tissues, concentrations in plasma might not be appropriate to reflect the effect of inflammation. The observation that inflammation has a profound effect on LPV exposure (thereby increasing the potential for enhanced pharmacokinetic boosting) raises the question of whether this should be taken into account when prescribing other CYP3A4 drugs in COVID-19 patients, particularly for drugs with a narrow therapeutic index (NTI). Important examples are anticoagulants or antiplatelet agents which are often prescribed to COVID-19 patients due to the higher risk of thrombotic complications. Importantly, 12 patients were closely monitored when receiving direct oral anticoagulant treatment (DOAC) before and after acquiring COVID-19. The patients were maintained on the same dose of DOAC after starting LPV/r or darunavir/ritonavir, another strong CYP3A4 Received: 24 June 2020 Revised: 28 July 2020 Accepted: 7 August 2020