Tacrolimus toxicity due to enzyme inhibition from ritonavir

Snee, Isabel; Drobina, Joshua; Mazer‐Amirshahi, Maryann

doi:10.1016/j.ajem.2023.04.045

Cited by 7 publications

(4 citation statements)

References 4 publications

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“…Nirmatrelvir/ritonavir could also exhibit potential life-threatening interactions in individuals on immunosuppressants which are mainly metabolized by CYP3A. As one immunosuppressant metabolized by CYP3A, tacrolimus have been reported to have significant interactions with nirmatrelvir/ritonavir in some cases, most were from patients with solid organ transplant ( Berar et al, 2022 ; Cadley et al, 2022 ; Kwon et al, 2022 ; Prikis and Cameron, 2022 ; Shah et al, 2022 ; Chen et al, 2023 ; Modi et al, 2023 ; Sindelar et al, 2023 ; Snee et al, 2023 ; Young et al, 2023 ; Zaarur et al, 2023 ). These patients presented with different symptoms including nausea, vomiting, fatigue, weakness, loss of appetite, abdominal pain, slowed speech, and peripheral neuropathy after they took nirmatrelvir/ritonavir without discontinuing tacrolimus.…”

Section: Discussionmentioning

confidence: 99%

“…Devresse and others used a standard management strategy of tacrolimus dose adaptation (discontinuation of tacrolimus 12 h before the start of nirmatrelvir/ritonavir) for a case series of 14 kidney transplant recipients with COVID-19, no acute kidney injury was observed during the treatment course and tacrolimus was resumed 6 days later ( Devresse et al, 2022 ). When patients present toxic symptoms and/or signs, tacrolimus must be discontinued and CYP inducers (phenytoin or rifampin) can be used to reverse the toxicity, which has been reported by some researchers ( Cadley et al, 2022 ; Kwon et al, 2022 ; Shah et al, 2022 ; Sindelar et al, 2023 ; Snee et al, 2023 ; Xiong et al, 2023 ). However, the use of CYP inducers might compromise the effectiveness of nirmatrelvir/ritonavir treatment by increasing the metabolism of nirmatrelvir.…”

Section: Discussionmentioning

confidence: 99%

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Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19

Zhang,

Han

et al. 2024

Front. Pharmacol.

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Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19

Zhang,

Han

et al. 2024

Front. Pharmacol.

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“…The publications that did not explicitly describe the use of pharmacoenhancement were also excluded. After extensive screening, a total of 24 publications in which CYP inducers were used to counteract supratherapeutic concentrations of CNIs were identified as illustrated in Figure 8 below [13][14][15][16][17][18][19][20][21][22][23]26,[31][32][33][34][35][36][37][38][39][40][41]. These publications described 34 distinct clinical cases in which pharmacoenhancement was used to treat supratherapeutic concentrations of TAC (91.2% of cases) and CsA (8.8% of cases).…”

Section: Analysis Of Case Reportsmentioning

confidence: 99%

“…Since patients depend on these drugs over long periods without sustainable therapeutic drug monitoring measures, they constantly face a potential risk of supratherapeutic concentrations. This risk increases substantially when patients are inadvertently exposed to CYP 3A4 inhibitors [13][14][15][16][17][18]. In hospitalized patients, cases of iatrogenic overdoses have been reported [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Rescue Therapy for Supratherapeutic Concentrations of Calcineurin Inhibitors Using Potent Cytochrome P450 Inducers

Duwor,

Enthofer,

Ganter

et al. 2024

Pharmacoepidemiology

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Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity.

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Nirmatrelvir+ritonavir/tacrolimus interaction

2023

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Tacrolimus toxicity due to enzyme inhibition from ritonavir

Cited by 7 publications

References 4 publications

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19

Rescue Therapy for Supratherapeutic Concentrations of Calcineurin Inhibitors Using Potent Cytochrome P450 Inducers

Nirmatrelvir+ritonavir/tacrolimus interaction

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