Current Status of Adverse Event Profile of Cyclosporine in Kidney, Stem Cell, and Heart Transplantations Using the Japanese Pharmacovigilance Database

Niinomi, Iku; Oyama, Saki; Inada, Ayaka; Wakabayashi, Tomohito; Iida, Takatoshi; Kambara, Hiroko; Uchida, Mayako; Sano, Yukako; Hosohata, Keiko

doi:10.7759/cureus.29383

Cited by 2 publications

(1 citation statement)

References 32 publications

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“…To the best of our knowledge, this is the first study exploring the demographics and outcomes of CNI intoxication using VigiBase™. The results from VigiBase™ affirm those obtained from previous epidemiological studies regarding the toxicity of CNIs [23,60,61]. Due to underreporting or unreported cases, the actual proportion of CNI intoxications in ICSRs at the global level remains unknown.…”

Section: Retrospective Analysis Of Cni Intoxications From Vigibase™ V...supporting

confidence: 79%

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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Section: Retrospective Analysis Of Cni Intoxications From Vigibase™ V...supporting

confidence: 79%

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

Duwor,

Enthofer,

Ganter

et al. 2024

Pharmacoepidemiology

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Spesolimab: A Review of the First IL-36 Blocker Approved for Generalized Pustular Psoriasis

Pathak,

Wang,

Dhillon

et al. 2024

Ann Pharmacother

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Objective: This article reviews clinical trial data that assesses the safety, efficacy, and clinical application of spesolimab, an interleukin-36 (IL-36) blocker, for the treatment of generalized pustular psoriasis (GPP). Data sources: A review of the literature was conducted using the search terms: “spesolimab,” “BI 655130,” and “spevigo” in MEDLINE (PubMed) and Clinicaltrials.gov from January 1, 1950 to October 31, 2023. Study selection and data extraction: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of spesolimab were included. Data Synthesis: In one phase 2 clinical trial evaluating single dose IV spesolimab for GPP flares at day 8, 54% of patients receiving spesolimab had a GPP physician global assessment (GPPGA) pustulation subscore of 0, and 43% had a GPPGA total score of 0 compared with 6% and 11% for the placebo group, respectively. Another phase 2 clinical trial assessing subcutaneous spesolimab found 23% of patients in low-dose, 29% in medium-dose, and 10% of high-dose spesolimab had flares by week 48 compared with 52% of the placebo group. Hazard ratios for time to GPP flare compared with placebo were 0.16 ( P = 0.0005), 0.35 ( P = 0.0057), and 0.47 ( P = 0.027) for the spesolimab groups, respectively. Infection rates were similar across treatment and placebo groups, and severe adverse events such as drug reactions with eosinophilia and systemic symptom (DRESS), cholelithiasis, and breast cancer occurred with spesolimab. Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs: Spesolimab is a first-in-class IL-36 monoclonal antibody receptor antagonist approved for the treatment of acute GPP flares. It is a safe and effective therapeutic agent in preventing future GPP flares, with no current comparator trials with other GPP agents. Conclusion: Spesolimab is a safe and effective treatment for acute GPP flares in adults. Future clinical trials can establish safety and efficacy compared with other agents.

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Current Status of Adverse Event Profile of Cyclosporine in Kidney, Stem Cell, and Heart Transplantations Using the Japanese Pharmacovigilance Database

Cited by 2 publications

References 32 publications

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

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

Spesolimab: A Review of the First IL-36 Blocker Approved for Generalized Pustular Psoriasis

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