Clinical Trial: Renal and Hepatic Clearance Following High-Dose Methotrexate in Childhood ALL
Study Status: Completed
Recruit Status: Completed
Study Type: Observational
Official Title: Pharmacokinetics: Renal and Hepatic Clearance Following High-Dose Methotrexate in Children With Acute Lymphoblastic Leukemia
Brief Summary:
High-dose methotrexate therapy (HDMTX) is an important part of treatment of childhood acute lymphoblastic leukemia (ALL). HDMTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. organic anion transporter 1B1 (OATP1B1) and reduced folate carrier (RFC)) are suggested to have a particular large impact. A serious limitation to the applicability of SNPs in prediction of MTX pharmacokinetics, however, is the substantial intra-individual variation in MTX clearance.
The intra-individual variation in MTX clearance is related to renal function but a large amount of a HDMTX dose also enters the liver, where it is metabolized to 7-hydroxy MTX and probably also undergoes enterohepatic circulation. Thus, the aim of this study is to determine the role of the liver and renal function in MTX pharmacokinetics, and evaluate the predictive potential of pharmacogenetic (e.g. the rfc SNP) and pharmacokinetic parameters of MTX elimination during HDMTX.
Detailed Summary:
Due to optimization of dosing and intensity of conventional anticancer drugs combined with early risk group classification and clinical trials the cure rates of childhood acute lymphoblastic leukemia (ALL) is now beyond 80%.
Methotrexate (MTX) is one of the most important drugs in the treatment of ALL and is a key component in all treatment phases. Infusions with high-dose methotrexate (HDMTX) are used in many treatment protocols for ALL but the optimal dose and infusion time remain undefined. The systemic clearance of MTX exhibits a large inter- and intra-individual variability and this cause several clinical problems. Fast MTX clearance has been associated with increased risk of relapse, whereas patients with slow MTX clearance have more side effects. In situations with extremely low MTX clearance it is necessary to administer very high doses of leucovorin in order to minimize toxicity; unfortunately treatment with this antidote can potentially rescue some of the cancer cells and thereby increase the risk of relapse.
Therapy with high-dose MTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. reduced folate carrier and the anion transporter 1B1, OATP1B1) are suggested to have a particularly large impact. A serious limitation, however, is that SNPs are difficult to use in the prediction of MTX pharmacokinetics when the intra-individual variation in MTX clearance has been shown to be up to six fold. In order to use genetic variation in a clinically settin
Sponsor: Rigshospitalet, Denmark
Current Primary Outcome: clearance [ Time Frame: within the first 6 months after recruitment has been completed ]
Original Primary Outcome: clearance [ Time Frame: within the first 6 months after recruitment completion ]
Current Secondary Outcome:
Original Secondary Outcome:
Information By: Rigshospitalet, Denmark
Dates:
Date Received: July 8, 2013
Date Started: March 2011
Date Completion:
Last Updated: July 14, 2013
Last Verified: July 2013
