Acute tacrolimus toxicity due to concomitant use of ritonavir (with nirmatrelvir as Paxlovid)

Case

A 68-year-old female presented to her local hospital with confusion, headache and tremors. She was on stable maintenance immune suppression for a lung transplant performed 6 years earlier. Her treatment included oral regimens of tacrolimus controlled-release 3 mg daily, mycophenolate mofetil 500 mg twice daily and prednisolone 5 mg daily. The patient’s medical history also included chronic obstructive pulmonary disease, hypertension and major depression. She had been vaccinated against COVID-19 and was not taking any medications that interact with tacrolimus, such as an azole. She was living at home and able to perform all activities of daily living independently.

The patient was diagnosed with COVID-19 six days before her presentation to hospital, with symptoms including dyspnoea, nausea, diarrhoea and mylagias. She was prescribed the combination of oral nirmatrelvir 300 mg and ritonavir 100 mg (Paxlovid) twice daily by her regular general practitioner (GP) and the medication was dispensed at her regular pharmacy. Neither the patient’s GP nor pharmacist identified the potential for interaction between tacrolimus and ritonavir (discussed below), and no adjustment was made to her tacrolimus dosage when nirmatrelvir and ritonavir were started. She completed 3 days of a 5-day treatment course before presentation to hospital.

Investigations in hospital demonstrated acute kidney injury, with an increase in serum creatinine concentration from 80 micromol/L measured the previous year (estimated glomerular filtration rate [eGFR] 50 mL/min/1.72m²) to 234 micromol/L (eGFR 23 mL/min/1.72m²). Her whole blood tacrolimus concentration was greater than 60 nanograms/mL (target trough concentration for this indication is 5 to 8 nanograms/mL).¹

The patient was diagnosed with acute tacrolimus toxicity. She was hospitalised for monitoring and tacrolimus was withheld by the medical team; however, the patient self-administered one dose of tacrolimus using her personal supply at the start of her admission. The clinical pharmacology service recommended the use of phenytoin in a tapered regimen for 3 days (loading dose given intravenously and then administered orally thereafter) with daily whole blood tacrolimus concentration monitoring. Phenytoin is an inducer of the cytochrome P450 enzyme CYP3A4, which is one of the pathways for tacrolimus metabolism, and has been used to decrease tacrolimus concentrations.²

The patient’s whole blood tacrolimus concentration decreased by 40% after 1 day, and by a further 50% in each of the subsequent 2 days with normalisation of serum creatinine and symptomatic improvement. The whole blood tacrolimus concentration was within the therapeutic range by day 4 and tacrolimus was restarted. The patient did not complete the course of nirmatrelvir and ritonavir, or receive any further specific treatment for COVID-19, but her regular dose of prednisolone was increased to 25 mg daily by the lung transplant team with a plan to wean back to 5 mg daily over 10 days.

 

Comment

Tacrolimus, a calcineurin inhibitor, is the cornerstone of maintenance immune suppression following allogeneic tissue transplantation. Tacrolimus is metabolised by CYP3A4 and CYP3A5 enzymes and transported by P-glycoprotein from the blood back into the intestines, so drugs that affect these pathways can alter whole blood tacrolimus concentrations. Tacrolimus toxicity presents with renal, neurological and gastrointestinal features.¹

Nirmatrelvir (in combination with ritonavir) is indicated for the treatment of COVID-19, reducing the need for hospitalisation when administered within the first 5 days of symptoms.³ Nirmatrelvir works by binding to the SARS-CoV-2 3CL protease to prevent viral replication. To boost plasma concentrations, it is taken with ritonavir, a CYP3A4 inhibitor that blocks the metabolism of nirmatrelvir. Ritonavir itself is inactive against SARS-CoV-2.⁴

In addition to inhibiting CYP3A4, ritonavir is also a P-glycoprotein inhibitor. Therefore, ritonavir inhibits the metabolism of tacrolimus and its reabsorption into the intestinal lumen. If ritonavir is co-administered with tacrolimus, it can lead to a rapid increase in the tacrolimus concentration. A significant dose reduction of tacrolimus is required to maintain the whole blood tacrolimus concentration within the therapeutic range.⁵ Adjustment of tacrolimus dosing should be done under the guidance of an experienced transplant physician in a setting where daily whole blood tacrolimus concentrations can be reliably measured. Tacrolimus dose reduction strategies have previously been described.⁶ If dose reduction of tacrolimus is not possible, alternative antiviral options for COVID-19 should be used, such as intravenous remdesivir.

 

Conclusion and recommendations

Solid organ transplant recipients have complex medication regimens. It is important to be vigilant for potential drug interactions when introducing a new medication, particularly if the patient is using a drug with a narrow therapeutic index, such as tacrolimus. It is also important that patients are educated about the potential for drug interactions and signs of toxicity, and notified when their medication regimen is being changed. Drugs that are being withheld or ceased should be removed from the patient’s medication supplies to avoid inadvertent administration.

For patients requiring antiviral treatment for COVD-19, the University of Liverpool COVID-19 drug interactions checker is considered the gold standard resource for advice on drug interactions. If there is concern that a serious drug interaction may occur in a patient on tacrolimus, expert advice from the transplant service should be sought.

In patients on tacrolimus who require antiviral treatment for COVID-19, remdesivir may be preferred over nirmatrelvir and ritonavir, because of the complexity of adjusting tacrolimus dosing and the need for daily whole blood tacrolimus concentration monitoring if nirmatrelvir and ritonavir are used.

Patient consent for publication of this case study was obtained by the authors.

Conflicts of interest: David Darley has received a travel grant from the Transplant Society of Australia and New Zealand. Evan Browne was the Clinical Pharmacology Trainee participant on the Australian Prescriber Editorial Advisory Committee at the time of writing. He was excluded from editorial decision-making related to the acceptance and publication of this case study. Cameron White and Bridin Murnion have no conflicts of interest to declare.

This article is peer reviewed.

 

References

1. Araya AA, Tasnif Y. Tacrolimus. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. [cited 2024 May 21]
2. Kwon EJ, Yun GA, Park S, Kim S, Chae DW, Park HS, et al. Treatment of acute tacrolimus toxicity with phenytoin after Paxlovid (nirmatrelvir/ritonavir) administration in a kidney transplant recipient. Kidney Res Clin Pract 2022;41:768-70.
3. Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 2022;386:1397-408.
4. Nirmatrelvir and ritonavir for COVID-19. Aust Prescr 2022;45:61.
5. Liverpool Drug Interactions Group. COVID-19 Drug Interactions checker. University of Liverpool; 2024. [cited 2024 Oct 17]
6. Lemaitre F. Yes We Can (Use Nirmatrelvir/Ritonavir Even in High Immunological Risk Patients Treated with Immunosuppressive Drugs)! Clin Pharmacokinet 2022;61:1071-3.