lung transplant medication and CYP interactions

The azole agents are commonly used agents in recipients of lung transplants (LTs) for both prophylaxis and treatment of fungal infections after LT, and awareness must be given to decreasing tacrolimus and cyclosporine dose when initiating or increasing the dose of the azole agent because of drug-drug interactions (choice C is correct). The usual maintenance immunosuppressive regimen after LT consists of a three-prong approach with a calcineurin agent, usually tacrolimus but occasionally cyclosporine; a cell cycle inhibitor agent, usually mycophenolate mofetil but occasionally azathioprine; and corticosteroids, usually prednisone. Tacrolimus and cyclosporine are selective inhibitors of calcineurin, a calciumand calmodulin-dependent phosphatase. The class of drugs, calcineurin inhibitors (CNIs), results in impaired transcription of IL-2 and other T-lymphocyte cytokines and work by suppressing cell-mediated immunity. Tacrolimus binds to FK-binding cytoplasmic cellular proteins that then bind to calcineurin. This results in the inhibition of translocation of transcription factors, leading to reduced transcriptional activation of cytokine genes for IL-2, tumor necrosis factor α, IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor, and interferon-γ. The final effect is a reduction in T-lymphocyte proliferation, primarily T helper cells.

Tacrolimus and cyclosporine are metabolized via cytochrome P450 (CYP3A4/5) enzymes in the liver, although there may be a small amount of gut metabolism. Because tacrolimus is a substrate for CYP3A4/5 enzymes, any drug that is metabolized by these enzymes or that affects metabolism by these enzymes can potentially interact with CNIs, and toxicity can develop. If the CYP3A4/5 inhibitor or inducer drug cannot be avoided, dosing adjustments and close monitoring are required.

Examples of strong inhibitors of P450 3A include the azoles and many antiviral agents. The tacrolimus and cyclosporine dose must be decreased when initiating or increasing the dose of the azole agent and must be increased when decreasing the dose or discontinuing the azole agents. Itraconazole, posaconazole, and voriconazole have the greatest effect; fluconazole, slightly less; and isavuconazole, the least. In addition, blood levels of tacrolimus must be closely monitored. In general, the commonly added macrolide for immunomodulation for chronic lung allograft dysfunction, azithromycin, does not require a dose adjustment.

Attention must be given to COVID-19 infection and the use of nirmatrelvir/ritonavir. Patients who have received transplants are at high risk for COVID-19 morbidity and mortality owing to immunosuppression and perhaps owing to decreased vaccine efficacy. Currently, with the newer COVID-19 variants, nirmatrelvir/ritonavir is one of the few antiviral agents that is still useful in treatment of infection due to COVID-19. The effect of nirmatrelvir/ritonavir, particularly the ritonavir component, on tacrolimus levels is dramatic, with the increase in the area under the curve of 1.8to 20-fold, often resulting in severely supratherapeutic levels and complications (eg, renal failure, posterior reversible encephalopathy syndrome, seizures, and death). Recent recommendations now allow for use of this agent with very careful monitoring of CNI levels and a significant CNI dose reduction (choice B is incorrect), and/or sometimes a short period of discontinuation of tacrolimus given the profound interaction. It is often helpful to make these decisions in collaboration with the transplant pharmacy clinicians, and CNI levels have to be monitored frequently.

Examples of inducers of CYP3A4/5 encountered when treating recipients of LTs include the rifamycin class of drugs, such as rifampin and less so rifabutin and rifapentine; the phenytoin-based drugs; the cystic fibrosis transmembrane conductance regulator modulators used in patients with cystic fibrosis; phenobarbital; and, to a smaller extent, even St. John's wort. Therefore, when using these drugs, an increase in the tacrolimus dose in addition to close monitoring of blood levels would be required.1

Footnotes

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