Paxlovid (Nirmatelvir/Ritonavir) and Tacrolimus Drug-Drug Interaction in a Kidney Transplant Patient with SARS-2-CoV infection: A Case Report

Prikis, Marios; Cameron, Alexandra

doi:10.1016/j.transproceed.2022.04.015

Cited by 54 publications

(50 citation statements)

References 5 publications

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“…An episode of inflammation related to clinical infectious events may contribute to increase tacrolimus levels by altering plasma protein binding; (3) inflammation also induces transcriptional inhibition of drug-metabolizing enzymes, including CYP, and transporters, resulting in modulation of tacrolimus pharmacokinetics; (4) liver and renal function that may have already been impaired by the infection or antiviral treatment. − The clearance of tacrolimus would be greatly reduced, and its elimination half-life would also be increased. Similar interactions between nirmatrelvir/r and tacrolimus in the transplant setting have recently been reported. , …”

Section: Discussionsupporting

confidence: 73%

“…Similar interactions between nirmatrelvir/r and tacrolimus in the transplant setting have recently been reported. 36,37 From a pharmacokinetic point of view, the first dosage of nirmatrelvir and ritonavir was performed 78 h after discontinuation of this treatment and 64 h after restarting tacrolimus. Because ritonavir is mainly hepatically cleared, its half-life would remain relatively stable in renal failure patients, at approximately 5 h. 27 When referring to patients with severe renal impairment, the elimination half-life of nirmatrelvir is approximately 13 h. 38 If we attempt to extrapolate the values on discontinuation of nirmatrelvir/r, using a simple monocompartmental model, the estimated concentrations of nirmatrelvir and ritonavir upon reinstatement of tacrolimus would be approximately at 15 μg/mL and 240 μg/mL, respectively.…”

Section: Discussionmentioning

confidence: 99%

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A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

Guyon

Novion

Fulda

et al. 2022

J. Am. Soc. Mass Spectrom.

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Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

Guyon

Novion

Fulda

et al. 2022

J. Am. Soc. Mass Spectrom.

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“…By inhibiting the transport and enzymatic pathways required for tacrolimus absorption and metabolism, ritonavir has the potential to significantly increase tacrolimus exposure within the systemic circulation, resulting in potential drug-related adverse effects. There are isolated reports of drug-drug interactions between nirmatrelvir/ritonavir and tacrolimus in the adult kidney transplant population [1]. However, there are currently no published reports on the interaction between tacrolimus and nirmatrelvir/ritonavir in the pediatric population.…”

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confidence: 99%

Elevated tacrolimus levels after treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19 infection in a child with a kidney transplant

2022

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Background Paxlovid (nirmatrelvir/ritonavir) is a novel drug available under emergency use authorization by the Food and Drug Administration for the treatment of COVID-19 infection. Tacrolimus, a calcineurin inhibitor, is commonly used as an immunosuppressant medication in children with kidney transplants. While tacrolimus is metabolized by the cytochrome P450 system (CYP3A4), ritonavir is a potent CYP3A4 inhibitor. There is a paucity of data regarding the drug-drug interaction between nirmatrelvir/ritonavir and tacrolimus in children with kidney transplants. Case-Diagnosis/Treatment This is a case report of a 14-year-old female with a history of a kidney transplant, maintained on tacrolimus and prednisone, who starts nirmatrelvir/ritonavir for a COVID-19 infection. She subsequently develops supratherapeutic tacrolimus levels and an increase in serum creatinine. Her tacrolimus was held, and the nirmatrelvir/ritonavir was stopped. Over time, her kidney function returned to baseline, her tacrolimus levels returned to the therapeutic goal, and her tacrolimus was resumed. Conclusions Our case report highlights the strong interaction with concomitant use of tacrolimus and nirmatrelvir/ritonavir in a pediatric kidney transplant recipient and the development of supratherapeutic tacrolimus levels. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to a pediatric patient currently on tacrolimus.

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“…Tacrolimus can be metabolized by CYP3A4 enzyme, which has been inhibited by ritonavir. 163 Moreover, Zhou et al . warned of the possible risk of host mutagenesis after treatment with molnupiravir because of the homogeneity of RNA and DNA precursors utilized by both virus and host.…”

Section: Concluding Remarks: Challenges and Future Perspectivesmentioning

confidence: 99%

Recent advances in small-molecular therapeutics for COVID-19

Zhong

Zhao

Peng

et al. 2022

Precision Clinical Medicine

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The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural protein (e.g. spike protein), non-structural protein (e.g. RdRp, Mpro, PLpro, helicase, NSP14, and NSP16), host protease and endosomal, as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. We here present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.

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Paxlovid (Nirmatelvir/Ritonavir) and Tacrolimus Drug-Drug Interaction in a Kidney Transplant Patient with SARS-2-CoV infection: A Case Report

Cited by 54 publications

References 5 publications

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

Elevated tacrolimus levels after treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19 infection in a child with a kidney transplant

Recent advances in small-molecular therapeutics for COVID-19

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