Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Pea, Federico; Baccarani, Umberto; Tavio, Marcello; Cojutti, Pier Giorgio; Adani, Gian Luigi; Londero, Angela; Baraldo, Massimo; Franceschi, Loretta; Furlanut, Mario; Viale, Pierluigi

doi:10.1345/aph.1l330

Cited by 25 publications

(14 citation statements)

References 14 publications

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“…In some studies, a prompt reduction in the immunosuppressive drug dose was recommended to prevent overexposure and maintain therapeutic levels. 18,24,27 In a case report of a liver transplant patient, Pea et al 24 showed that a prompt reduction of the everolimus dosage from 0.75 mg twice daily to 0.25 mg/d allowed for therapeutic levels to be achieved. Similarly, Marty et al 18 noted in an allogenic hematopoietic stem cell transplantation that none of the patients with an empiric 90% sirolimus and 50% tacrolimus dosage reduction at the start of treatment with voriconazole had immunosuppressant levels above the therapeutic range during coadministration.…”

Section: Discussionmentioning

confidence: 99%

“…18,24,27 Similarly, after the discontinuation of voriconazole, interaction also disappeared immediately, requiring an anticipated increase in the everolimus dose at the time of voriconazole withdrawal to avoid infratherapeutic levels. Nevertheless, some studies suggest that interaction takes much longer to disappear after azole discontinuation.…”

Section: Discussionmentioning

confidence: 99%

“…On reviewing our data, we have recently noticed an increase in the number of lung transplant patients cotreated with voriconazole and everolimus. To date, very few studies have assessed this pharmacokinetic interaction, with only 2 case reports 24,25 and a retrospective study 26 with a limited number of lung transplant patients (9 in total). There are no recommendations regarding the management of patients receiving both drugs, or by what percentage the everolimus dose should be reduced when voriconazole is added during its concomitant use.…”

Section: Introductionmentioning

confidence: 99%

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Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients

Macías

Garrido

Pazos

et al. 2016

Therapeutic Drug Monitoring

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Oral voriconazole is a strong inhibitor of everolimus metabolism, requiring a dose reduction of around 87%. At the time of azole withdrawal, the dose should be increased to achieve C0/D ratio values similar to the initial situation. In our clinical practice, for a safe coadministration, a preemptive decrease to 75% of everolimus dose with the first azole prescription is recommended. Close monitoring of the everolimus concentrations and corresponding dosage adjustments are necessary until the target levels are achieved during both periods.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients

Macías

Garrido

Pazos

et al. 2016

Therapeutic Drug Monitoring

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“…Everolimus is distributed by P-glycoproteins and metabolized by CYP3A4 [44,45]. Although the pharmacokinetic profiles of stattic have not been clarified, there is no denying that the interactions between everolimus and stattic are due to pharmacokinetic actions.…”

Section: Discussionmentioning

confidence: 99%

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Yamamoto

Uda

Mukai

et al. 2013

J Exp Clin Cancer Res

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BackgroundMammalian target of rapamycin (mTOR) inhibitors are associated with dermatological adverse events. The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 (STAT3) protein and the dermatological adverse events associated with the mTOR inhibitor everolimus.MethodsWe evaluated the effects of STAT3 activity and related signal transduction activities on everolimus-induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST-8 assay, and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis. Apoptosis was evaluated using an imaging cytometric assay.ResultsThe cell growth inhibitory effects of everolimus were enhanced by stattic or STA-21, which are selective inhibitors of STAT3, treatment in HaCaT cells, although such effects were not observed in Caki-1 and HepG2 cells. Phosphorylation at tyrosine 705 of STAT3 was decreased by treatment with everolimus in a dose-dependent manner in HaCaT cells; in contrast, phosphorylation at serine 727 was not decreased by everolimus, but slightly increased. Furthermore, we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of STAT3 in HaCaT cells resisted the cytostatic activity of everolimus.ConclusionsThese findings suggest that STAT3 activity may be a biomarker of everolimus-induced dermatological toxicity.

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“…The expected profile for PK DDI, with strong metabolism of the drug, has already been confirmed in the first case reports published. 73 TDM plays a crucial role in the monitoring of changes in ERL concentration. PK differences between ERL and SRL favor the adaptation of ERL doses during DDI management.…”

Section: Antiproliferative Effects and Cancersmentioning

confidence: 99%

The Role of Everolimus in Lung and Liver Transplantation

2011

Clinical Medicine Reviews in Therapeutics

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Everolimus (ERL) is a recently developed mTOR inhibitor. This rapamycin analog is used to prevent acute rejection during kidney and heart transplantation. We review here published clinical trials and experiences concerning potential applications of ERL in liver and lung transplantation. Most of the data concern conversion for rescue situations, but a small number of studies have been conducted in de novo patients. In most cases, everolimus was used to spare renal function and to minimize calcineurine inhibitor use, but also, due to the antiproliferative properties of the drugs of this class, to control malignancy. Safety issues are an important consideration when deciding whether to maintain a patient on treatment. Therapeutic drug monitoring is strongly recommended, to achieve a mean whole-blood trough concentration of 6 ng/mL, with doses of 0.5 to 1.5 mg administered twice daily. There is solid evidence that ERL is a feasible and effective treatment, for a selected subset of patients, in the contexts of liver and lung transplantation.

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Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Abstract: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Cited by 25 publications

References 14 publications

Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients

Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

The Role of Everolimus in Lung and Liver Transplantation

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