The interaction between nirmatrelvir/ritonavir and sirolimus: a case report of a kidney recipient with renal insufficiency and COVID-19

Abstract

Nirmatrelvir/ritonavir is a novel drug combination authorized by the US Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). This report describes the case of a patient with a prior history of kidney transplantation who received nirmatrelvir/ritonavir. In this case, sirolimus use was successfully stopped before nirmatrelvir/ritonavir treatment, and the nirmatrelvir/ritonavir trough concentration was determined. During nirmatrelvir/ritonavir treatment, the sirolimus trough concentration remained stable. This case highlights the risk associated with the concomitant administration of sirolimus and nirmatrelvir/ritonavir. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to kidney transplant recipients currently receiving sirolimus, with caution exercised based on creatinine clearance.

Introduction

Paxlovid (nirmatrelvir/ritonavir) is a novel drug available under emergency use authorization by the US Food and Drug Administration for the treatment of COVID-19. Ritonavir is a potent CYP3A4 inhibitor. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), is commonly used to maintain immunosuppression after renal transplantation. Sirolimus is metabolized by the cytochrome P450 system (CYP3A4, CYP3A5). Considering the drug–drug interactions between nirmatrelvir/ritonavir and sirolimus following kidney transplantation, a series of medication adjustments were performed.

Case presentation

This case involved a 44-year-old man who underwent kidney transplantation for renal insufficiency (creatinine 382.3 µmol/L) 20 years before presentation. The patient was undergoing maintenance treatment with sirolimus, mycophenolate mofetil, and prednisone. The patient was diagnosed with COVID-19 and treated with nirmatrelvir/ritonavir (150 mg/100 mg). The trough sirolimus concentration in this patient ranged 3.99 to 6.76 ng/mL. To avoid drug–drug interactions associated with the concomitant use of sirolimus and nirmatrelvir/ritonavir, sirolimus was withheld during 5 days of nirmatrelvir/ritonavir treatment. During nirmatrelvir/ritonavir treatment, the patient’s trough sirolimus concentration ranged 6 to 7 ng/mL. At the same time, nirmatrelvir/ritonavir levels were also determined by LC-MS/MS. On the third day of nirmatrelvir/ritonavir treatment, the nirmatrelvir trough concentration increased to 7370 ng/mL, and the ritonavir trough concentration increased to 1650 ng/mL (shown in Figure 1 and Table 1). Over time, his sirolimus levels gradually decreased. The interaction between nirmatrelvir/ritonavir and sirolimus in this patient with renal insufficiency was also studied. The reporting of this study conforms to the CARE guidelines. ¹

Table 1.

Sirolimus and nirmatrelvir/ritonavir doses in a kidney transplant recipient during hospitalization

Hospital Day	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8
Sirolimus (mg)	2-2	2-2	/	/	/	/	/	/
N/R (mg)	NA	NA	0150/100	150/100150/100	150/100150/100	150/100150/100	150/100150/100	150/100150/100

N/R: nirmatrelvir/ritonavir; N/A: not applicable.

Figure 1.

Sirolimus, nirmatrelvir/ritonavir, serum creatinine during hospital stay of kidney transplantation recipient.

Discussion

According to the drug information, ² nirmatrelvir/ritonavir is not recommended for patients with severe renal insufficiency (estimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m²). When nirmatrelvir metabolism is inhibited by ritonavir, nirmatrelvir is eliminated via renal excretion. The patient’s eGFR was 15 mL/minute/1.73 m², and thus, the elimination of nirmatrelvir was affected. The effect of renal insufficiency on ritonavir elimination is negligible. The patient was not re-examined for COVID-19 nucleic acid levels, and the efficacy of nirmatrelvir/ritonavir was not determined. At the same time, the patient had cytomegalovirus infection, but no intervention was performed.

In one study ³ involving patients receiving continuous renal replacement therapy (CRRT), two patients with severe renal injury received nirmatrelvir/ritonavir (150 mg/100 mg) q12h, and their trough concentrations were 5294.83  and 7576.83 ng/mL, respectively. Importantly, these patients’ nirmatrelvir concentrations greatly exceeded the specifications by nearly 10-fold (peak concentrations of 1600 and 2369 ng/mL were observed in patients with normal renal function and severe renal impairment, respectively). ²

To date, several studies have described the administration strategy of tacrolimus and nirmatrelvir/ritonavir, but no reports identified the optimal administration strategy for mTOR inhibitors such as everolimus and sirolimus in combination with nirmatrelvir/ritonavir or other ritonavir preparations. In clinical trials, patients receiving drugs highly dependent on CYP3A4, such as sirolimus and everolimus, were excluded. Therefore, we must rely on information on drug interactions for treatments with similar properties in terms of CYP3A-mediated metabolism and P-glycoprotein–mediated transport inhibition to perform initial dose adjustment for solid organ transplant recipients receiving mTOR inhibitors when starting nirmatrelvir/ritonavir. For everolimus and sirolimus, few retrospective reports are available to provide guidance on appropriate dosing strategies. A study on the dose requirements of sirolimus in ritonavir combination therapy for patients with HIV recommended 1/20^th to 1/10^th of the typical dose of sirolimus. ⁴

The effect of renal impairment on the pharmacokinetics of sirolimus is unknown, but sirolimus or its metabolites are rarely excreted by the kidneys (only 2.2%), and thus, renal impairment does not necessitate adjustment of the dose of sirolimus. ⁵

Lemaitre et al. investigated therapeutic drug monitoring and dosage adjustments for immunosuppressive drugs in patients receiving nirmatrelvir/ritonavir for COVID-19. It is recommended ⁶ to stop mTOR inhibitors 12 hours before initiating nirmatrelvir/ritonavir treatment, take one-eighth of the usual daily dose (DD) on days 1, 3, and 5 of treatment, restart the usual daily dose on day 7, and perform therapeutic drug monitoring (TDM) on day 3. We should continue to perform TDM after resuming the usual daily dose.

“Management of nirmatrelvir/ritonavir drug interactions in the Treatment of Covid-19 patients: Guidelines of the French Society for Pharmacology and Therapeutics (SFPT)” ⁷ states that nirmatrelvir/ritonavir increases sirolimus exposure by 11-fold. It is recommended to give one-eighth of the usual DD on days 1, 3, and 5 after nirmatrelvir/ritonavir discontinuation. The DD can usually be resumed on day 7. At the same time, the blood concentration was monitored. Patients with COVID-19 are at high risk of progression to severe disease. ⁸ Our experience with this patient leads us to conclude that sirolimus should be withheld during nirmatrelvir/ritonavir treatment.

Conclusions

In this case report, sirolimus use was successfully stopped before nirmatrelvir/ritonavir treatment. During nirmatrelvir/ritonavir use, the sirolimus trough concentration remained stable. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to kidney transplant recipients currently receiving sirolimus with particular focus given to creatinine clearance.