Response to "CYP450 3A4/5 Containment During SARS-CoV-2 Infection".

To the Editor,

We read with great interest the recent letter by Terrier et al. regarding the impact of severe acute respiratory syndrome–coronavirus 2 (SARS‐CoV‐2) infection on cytochromes P450 (CYP450)–mediated metabolism in coronavirus disease 2019 (COVID‐19) patients. The authors highlight the role of inflammation in CYP450 inhibition in COVID‐19 patients on the basis of their recent work and putting into perspective our recent publication on midazolam pharmacokinetics in patients in the intensive care unit with COVID‐19. , Our conclusions are the same and we consider that great attention should be paid to these patients when they are treated with drugs using this metabolic pathway. For example, a work has recently been published about the impact of SARS‐CoV‐2 infection on the pharmacokinetics of tacrolimus and shows that concentrations are greatly increased in these patients. We also observed the same phenomenon in seven hospitalized SARS‐CoV‐2–infected transplant patients with longitudinal follow‐up of their tacrolimus concentrations. As shown in Figure , all patients experienced increased concentrations within 2 weeks after the positive SARS‐CoV‐2 reverse transcription polymerase chain reaction, leading to systematically decreasing the daily dosage, or in some cases stopping the tacrolimus regimen for a few days. The increase in concentrations was associated with an increase in C‐reactive protein level, which was the follow‐up inflammatory marker. We observed these pharmacokinetic modifications as well in patients with severe COVID‐19 requiring a hospitalization in the intensive care unit as in less severe patients potentially followed up on an outpatient basis. We have previously shown that the concentration of lopinavir, also a CYP450 substrate, was strongly increased in patients with COVID‐19 regardless of the severity of the disease. All these data show that patients with COVID‐19 treated for chronic conditions with CYP450‐metabolized drugs should be monitored particularly closely to avoid overdose and toxicity. Some therapeutic classes appear to be particularly at risk, such as immunosuppressive drugs, calcium channel blockers, azole antifungal agents, β‐hydroxy‐β‐methylglutaryl‐CoA (HMG‐CoA) reductase inhibitors (statins), vitamin K antagonists, non–vitamin K antagonist oral anticoagulants, and some antipsychotic and antidepressant drugs. In summary, patients with COVID‐19 with chronic conditions treated with CYP450‐metabolized drugs should be closely followed up, and, when possible, therapeutic drug monitoring of these drugs should be proposed to prevent the risk of overdose and associated adverse events.

Figure 1

Impact of inflammation on tacrolimus concentrations and monitoring. The curved lines represent the longitudinal follow‐up of tacrolimus concentrations. The dots represent the daily doses administered. The histograms represent the C‐reactive protein concentrations. The straight full lines represent the date of positive SARS‐CoV‐2 reverse transcription polymerase chain reaction. The dotted lines represent the beginning of symptoms. The dashed lines represent the date of transplant. The black double arrows represent the hospitalization in the ICU. The gray double arrow represents the administration of a drug that could inhibit the CYP450 3A4/5 activity. (a) Representation of the axis label. (b–h) Representation of the longitudinal follow‐up of tacrolimus concentrations for seven patients hospitalized in Nantes Hospital. CYP450 3A 4/5, cytochrome P450 3A 4/5 isozymes; D, Day; ICU, intensive care unit; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.

FUNDING

No funding was received for this work.

CONFLICT OF INTEREST

The authors declared no competing interests for this work.