Document Detail


A pharmacokinetic/pharmacodynamic model of tumor lysis syndrome in chronic lymphocytic leukemia patients treated with flavopiridol.
MedLine Citation:
PMID:  23300276     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Flavopiridol, the first clinically evaluated cyclin-dependent kinase inhibitor, shows activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.
EXPERIMENTAL DESIGN: A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early-phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.
RESULTS: Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy less than 10 cm or 10 cm or more during the first 2 treatments was 0.111 (SE% 13.0%) and 0.265 (SE% 17.9%), respectively, when flavo-G area under the plasma concentration versus time curve was at its median value in whole-patient group.
CONCLUSIONS: This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine whether the associations between TLS, gender, and glucuronide metabolites are relevant in patients with chronic lymphocytic leukemia treated with other cyclin-dependent kinase inhibitors.
Authors:
Jia Ji; Diane R Mould; Kristie A Blum; Amy S Ruppert; Ming Poi; Yuan Zhao; Amy J Johnson; John C Byrd; Michael R Grever; Mitch A Phelps
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-08
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  19     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-05     Completed Date:  2013-10-31     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1269-80     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacokinetics,  therapeutic use*
Female
Flavonoids / pharmacokinetics,  therapeutic use*
Follow-Up Studies
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / complications,  drug therapy*,  pathology
Male
Maximum Tolerated Dose
Models, Biological*
Neoplasm Recurrence, Local
Piperidines / pharmacokinetics,  therapeutic use*
Prevalence
Prognosis
Tissue Distribution
Tumor Lysis Syndrome / epidemiology*,  etiology
United States / epidemiology
Grant Support
ID/Acronym/Agency:
5KL2RR025754/RR/NCRR NIH HHS; KL2 RR025754/RR/NCRR NIH HHS; P01 CA081534/CA/NCI NIH HHS; P30 CA016058/CA/NCI NIH HHS; U01 CA076576/CA/NCI NIH HHS; U01 GM092655/GM/NIGMS NIH HHS; U01CA76576/CA/NCI NIH HHS; U01GM092655/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Flavonoids; 0/Piperidines; 45AD6X575G/alvocidib
Comments/Corrections

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