Withhold the immunosuppressive drugs and measure their levels before prescribing nirmatrelvir/ritonavir (Paxlovid) in patients who have received solid organ transplants, suggests a small case series of two patients published in Open Forum Infectious Diseases.¹ It also recommends close monitoring of drug levels during therapy and at least twice in a week after restarting the immunosuppressant when treatment with nirmatrelvir/ritonavir ends.

In this article, the authors describe two transplant recipients - a 40-year-old male recipient of a pancreas-kidney transplant and a 58-year-old female who had received bilateral lung transplant - who were on tacrolimus and were prescribed nirmatrelvir/ritonavir after testing positive for Covid-19 as outpatients. During the course of treatment, they were put on maintenance tacrolimus regimen. The patients subsequently developed tacrolimus toxicity, for which they needed hospitalization. They were treated with rifampicin for reversal of toxicity following which treatment with tacrolimus was re-initiated.

Nirmatrelvir/ritonavir is prescribed orally twice daily for five days as outpatient treatment. The National Institute of Health (NIH) COVID-19 treatment guidelines have cautioned about the likelihood of drug interactions with nirmatrelvir/ritonavir, which may at times be potentially fatal. These drug-drug interactions are mainly due to ritonavir.²

While some medications can be safely administered concomitantly with nirmatrelvir/ritonavir, some medications such as tacrolimus may need to be temporarily withheld during treatment with nirmatrelvir/ritonavir and for at least 2–3 days after treatment is completed. Either an alternative concomitant medication or Covid-19 treatment should be opted for, if it is not clinically possible to hold back the drug.

The authors write, “To our knowledge, we describe the first clinical descriptions of tacrolimus toxicity in conjunction with NIM-RTV, and the use of rifampin as an antidote.” Supratherapeutic levels of tacrolimus occur as a result of drug interaction between tacrolimus and nirmatrelvir/ritonavir due to irreversible CYP3A inhibition, which inhibits metabolism.

Hence, before prescribing nirmatrelvir/ritonavir to Covid-positive patients, physicians should carefully go through all medications that the patient may be taking, including over-the-counter drugs and herbal supplements, to assess any likely drug-drug interactions.

References

1. Rose DT, et al. Supratherapeutic tacrolimus concentrations with nirmatrelvir/ritonavir in solid organ transplant recipients requiring hospitalization: A case series using rifampin for reversal. Open Forum Infectious Diseases, 2022;, ofac238, https://doi.org/10.1093/ofid/ofac238.

2.     Ritonavir-Boosted Nirmatrelvir (Paxlovid). May 13, 2022. https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/