Polymorphisms and Busulfan Pharmacokinetic Study
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|ClinicalTrials.gov Identifier: NCT01257854|
Recruitment Status : Active, not recruiting
First Posted : December 10, 2010
Last Update Posted : December 18, 2017
|Condition or disease|
|Children Who Receive a Stem Cell Transplantation With Busulfan IV|
Most of the drugs used to treat cancer are metabolized by hepatic enzymes such as cytochrome P450 or Glutathion-S-Transferase (GST). These enzymatic pathways can be more or less active in the drug's metabolism according to the given polymorphism of each patient (pharmacogenomics).
The current hypothesis is that some functional polymorphisms of genes, which control important enzymes in Busulfan metabolism, contribute to the observed interindividual variability in PK of this drug. This variability can hence predict the resistance as well as the toxicity from a drug in patients who have cancer. The pharmacokinetic profile of different drugs, which have a hepatic metabolism, can be dramatically modified by these polymorphisms. Busulfan is a major drug used in the conditioning regimen before hematopoietic stem cell transplantation, particularly in children in whom total body irradiation has to be avoided. This drug has a narrow therapeutic index. At a lower systemic exposure than the targeted one, Busulfan has insufficient activity and hence an increased risk of transplant rejection and leukemic relapse.
At higher systemic exposures, the toxicity risk increases dramatically with an elevated incidence of hepatic veno-occlusive disease (VOD). Pharmacokinetic monitoring of Busulfan allows optimal dosing. The recommended doses are based on the weight, body surface area or age. Nevertheless, a majority of patients will still need an adjustment of the dose administered after their first dose: this will result in a cumulative systemic exposure that will be over or under therapeutic. Busulfan is metabolized principally by the GSTA1, as well as by other GST enzymes like the GSTM1 and GSTP1. These enzymes are present in the liver as well as in the intestinal cells and are up regulated in the digestive system of young children.With this study we will look for the polymorphism in GST genes, look at the Busulfan IV pharmacokinetics and finally look at the GST alpha enzyme activity and see if there is a correlation with clinical end points. This study will also study any correlation with other genes (repair DNA genes, CYP etc..) that could be correlated with Busulfan and/or cyclophosphamide. This study will also allow to do some DNA banking for future studies in genetics. This multicentric study is sponsor by the Swiss pediatric Oncology Group and is a European Bone and Marrow Transplantation study open in 6 countries (Switzerland, Canada, Italy, Holland, Tscèque republic, ). Pilot study are first analyze with St. Justine Hospital then with the other center at a later stage.
|Study Type :||Observational|
|Estimated Enrollment :||200 participants|
|Official Title:||Polymorphisms and Busulfan Pharmacokinetic Study in Pediatric Transplnatation|
|Study Start Date :||February 2008|
|Estimated Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||December 2018|
Busulfan, pharmacogenetic, pharmacokinetic, children
Children who receive Busulfan IV and have a pharmacokinetic of Busulfan
- polymorphisms in genes involved in Busulfan pathways correlation with pharmacokinetic [ Time Frame: 1 year post hematopoietic stem cell transplantation ]
- polymorphisms in genes involved in Busulfan pathways correlation with toxicity [ Time Frame: 1 year post hematopoietic stem cell transplantation ]
- polymorphisms in genes involved in Busulfan pathways correlation with survival [ Time Frame: 1 year post stem cell transplantation ]
Biospecimen Retention: Samples With DNA
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01257854
|Alberta children's hospital|
|Calgary, Alberta, Canada|
|Chu St Justine|
|Montreal, Quebec, Canada, H3T1C5|
|Hopital Rebert Debré|
|Hopital Cantonal de Genève|
|Geneva, Switzerland, 1206|
|Principal Investigator:||Marc Ansari, MD, PhD||Hopital Cantonal de Genève, Switzerland|