Acute Rejection and Massive Cyclosporine Requirements in Heart Transplant Recipients Treated With Rifampin

Dl, Modry; Eb, Stinson; Oyer, P E; Sw, Jamieson; Jc, Baldwin; Ne, Shumway

doi:10.1097/00007890-198503000-00022

Cited by 74 publications

(32 citation statements)

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“…Although many of the P450 enzymes are known to be inducible, CYP3A4 induction is probably the most important cause of documented induction-based interactions (Lin, 2006). For example, rifampin can precipitate breakthrough bleeding and contraception failure if administered with oral contraceptives (Back et al, 1980) and cause organ rejection if given with cyclosporine (Modry et al, 1985;Hebert et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Xu¹,

Zhou²,

Hayashi³

et al. 2011

Drug Metab Dispos

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Section: Introductionmentioning

confidence: 99%

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Xu¹,

Zhou²,

Hayashi³

et al. 2011

Drug Metab Dispos

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“…For drugs whose effect is produced primarily by the parent drug, induction would increase the drug's elimination, resulting in lower drug concentrations, and decrease the drug's pharmacological effect. For instance, rifampicin had caused acute transplant rejection in patients treated with cyclosporine, presumably because of induction of the CYP3A4-mediated metabolism of cyclosporine (1,2). Second, induction may create an undesirable imbalance between detoxification and activation as a result of increased formation of reactive metabolites, leading to an increase in the risk of metabolite-induced toxicity (3,4).…”

Section: Introductionmentioning

confidence: 99%

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

2006

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Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.

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“…When calcineurin inhibitors and rifampin are coadministered, increasing the dose of calcineurin inhibitors is essential in maintaining therapeutic blood levels, but this often fails and results in the induction of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) or graft rejection after solid organ transplantation [1][2][3][4][5][6]. Another option is the administration of agents which could compete with the activity of rifampin upon CYP 3A4.…”

mentioning

confidence: 99%

“…Increasing the dose of calcineurin inhibitors is not always effective, and the reduced levels can result in the induction of GVHD after allogeneic HSCT or graft rejection after solid organ transplantation [1][2][3][4][5][6]. An alternative to increasing the dose of calcineurin inhibitors is coadministration of an inhibitor and/or substrate of CYP 3A4.…”

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confidence: 99%

Overcoming the effect of rifampin on the tacrolimus metabolism by itraconazole administration in an allogeneic hematopoietic stem cell transplant recipient

et al. 2010

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Rifampin, one of the first-line agents for tuberculosis, has a great potential to induce the activity of the cytochrome P450 (CYP) enzyme, CYP 3A4, and lowers the concentration of calcineurin inhibitors such as tacrolimus and cyclosporine A (CsA). When calcineurin inhibitors and rifampin are coadministered, increasing the dose of calcineurin inhibitors is essential in maintaining therapeutic blood levels, but this often fails and results in the induction of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) or graft rejection after solid organ transplantation [1][2][3][4][5][6]. Another option is the administration of agents which could compete with the activity of rifampin upon CYP 3A4. We here present a case in which rifampin was coadministered with tacrolimus after allogeneic HSCT, and administration of oral-solution itraconazole successfully offset the effect of rifampin on the tacrolimus metabolism, resulting in the achievement of a therapeutic blood level of tacrolimus.A 50-year-old woman with myelodysplastic syndrome underwent bone marrow transplantation from an unrelated donor. Tacrolimus and short-term methotrexate were given for the prophylaxis of GVHD. Tacrolimus was given at an initial dose of 0.03 mg/kg by continuous intravenous infusion from day -1, and its dose was adjusted to maintain its blood level at 15-20 ng/ml during the first 4 weeks, followed by oral administration to maintain the blood level at 5-10 ng/ml. She developed acute GVHD of the skin on day 33 post-transplant, which was successfully treated with prednisolone. Prednisolone was given at a dose of 1 mg/kg for 7 days, then tapered, and discontinued on day 96 posttransplant. During prednisolone therapy, voriconazole at dose of 400 mg/day was orally given for the prophylaxis of fungal infection. Antifungal agents were not given thereafter. Around day 150 post-transplant, when tacrolimus was still being orally administered (3 mg/day) and its whole-blood trough level was around 5.5 ng/mL, pulmonary tuberculosis was diagnosed. Anti-tuberculosis chemotherapy consisting of rifampin (300 mg/day), isoniazid (300 mg/day), ethambutol (750 mg/day), and pyrazinamide (1200 mg/day) was initiated. Shortly after initiating this combination therapy, the trough level of tacrolimus became undetectable by automated microparticle enzyme immunoassay (minimum detectable level: 3.0 ng/ mL). Doubling the dose of tacrolimus to 6 mg/day failed to achieve a detectable level of tacrolimus. Oral-solution itraconazole was then initiated at a dose of 200 mg/day for the prophylaxis of fungal infection. The trough level of tacrolimus began to rise, and reached 5.7 ng/ml with 3 mg/ day of oral tacrolimus in 8 days after initiating itraconazole. The patient did not develop GVHD during or after the period of undetectable blood levels of tacrolimus, and fungal infection throughout the clinical course. The combination antituberculosis therapy was effective, and the pulmonary tuberculosis was cured after the 12-month therapy. Coa...

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Acute Rejection and Massive Cyclosporine Requirements in Heart Transplant Recipients Treated With Rifampin

Cited by 74 publications

References 0 publications

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Overcoming the effect of rifampin on the tacrolimus metabolism by itraconazole administration in an allogeneic hematopoietic stem cell transplant recipient

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