Pharmacoepidemiology of tacrolimus in pediatric liver transplantation

Riva, Natalia; Schaiquevich, Paula; Guido, P; Halac, Esteban; Dip, Marcelo; Imventarza, Oscar

doi:10.1111/petr.12982

Cited by 8 publications

(8 citation statements)

References 45 publications

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“…In this study, we found that children treated with CNI showed significantly lower serum magnesium levels and that they were significantly more likely to develop hypomagnesemia. This is in line with previous findings in children [ 31 , 32 , 33 , 34 ] and adults [ 21 ]. In adults and animal models, it was shown that hypomagnesemia is caused by renal magnesium wasting [ 20 , 21 , 35 ].…”

Section: Discussionsupporting

confidence: 94%

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors

et al. 2018

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Background: It was shown in animal models and adults that the epidermal growth factor (EGF) is involved in the pathophysiology of calcineurin inhibitor (CNI) induced renal magnesium loss. In children, however, the exact mechanism remains unclear, which was set as the purpose of the present study. Methods: Children with nephrotic syndrome and renal transplant children treated with CNI (n = 50) and non-CNI treated children (n = 46) were included in this study. Urine and serum samples were collected at three time points to determine magnesium, creatinine, and EGF. The magnesium intake was calculated from a food frequency questionnaire. Results: Serum Mg2+ and urinary EGF/creatinine were significantly lower in the CNI treated children, with significantly more CNI-treated children developing hypomagnesaemia. In the latter patients, the fractional excretion of magnesium (FE Mg2+) was significantly higher. Urinary EGF, age, renal function, and serum magnesium were independent predictors of the FE Mg2+. Only 29% of the children reached the recommended daily intake of magnesium. The magnesium intake did not differ between hypomagnesemic and normomagnesemic patients and was not a predictor of the FE Mg2+. Conclusions: In CNI-treated children who developed hypomagnesemia, the FE Mg2+ was increased. The urinary EGF concentration, age, and renal function are independent predictors of the FE Mg2+.

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Section: Discussionsupporting

confidence: 94%

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors

et al. 2018

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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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“…The present study was originally intended to evaluate a new immunosuppressive protocol in our hospital including the utilization of induction therapy to minimize the administration of steroids in pediatric patients who received the first liver transplantation. This study is comprised of patients included in a previous report 13 .…”

Section: Study Populationmentioning

confidence: 99%

“…Despite close individual monitoring, ADR and AR episodes are still detrimental to the patient´s quality of life. Limited information is available in the literature regarding the causes of inter-individual variability in tacrolimus pharmacodynamics in pediatric patients, and particularly in Latin-American liver transplant patients 12,13 . Specifically, identification of risk factors for AR and ADR to tacrolimus may help in reducing the frequency of complications after liver transplantation, and hence minimize the risk of graft loss, non-compliance, and death 14 .…”

Section: Introductionmentioning

confidence: 99%

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation

Riva

Dip

Halac

et al. 2018

Therapeutic Drug Monitoring

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Pharmacoepidemiology of tacrolimus in pediatric liver transplantation

Cited by 8 publications

References 45 publications

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors

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

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation

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