Vincristine pharmacodynamics and pharmacogenetics in children with cancer: A limited-sampling, population modelling approach

Moore, Andrew S., Norris, Ross, Price, Gareth, Nguyen, Thu, Ming, Ni, George, Rani, van Breda, Karin, Duley, John, Charles, Bruce and Pinkerton, Ross (2011) Vincristine pharmacodynamics and pharmacogenetics in children with cancer: A limited-sampling, population modelling approach. Journal of Paediatric and Child Health, 47 12: 875-882. doi:10.1111/j.1440-1754.2011.02103.x


Author Moore, Andrew S.
Norris, Ross
Price, Gareth
Nguyen, Thu
Ming, Ni
George, Rani
van Breda, Karin
Duley, John
Charles, Bruce
Pinkerton, Ross
Title Vincristine pharmacodynamics and pharmacogenetics in children with cancer: A limited-sampling, population modelling approach
Journal name Journal of Paediatric and Child Health   Check publisher's open access policy
ISSN 1034-4810
1440-1754
Publication date 2011-12-01
Sub-type Article (original research)
DOI 10.1111/j.1440-1754.2011.02103.x
Volume 47
Issue 12
Start page 875
End page 882
Total pages 8
Place of publication Oxford, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Formatted abstract
Background: Vincristine is a key component of many childhood cancer treatment regimens. Pharmacodynamic parameters such as clinical efficacy and toxicity may be influenced by polymorphisms of CYP3A.

Aim:
The aim of this study was to document CYP3A5 genotype, vincristine pharmacokinetics (PK) and neurotoxicity profile for 50 children with cancer and determine whether, in a population of Australian children, the CYP3A5 genotype influenced the pharmacodynamics of vincristine as reflected by peripheral neurotoxicity.

Methods:
Blood for PK analysis was collected after any single dose of vincristine and assayed using high performance liquid chromatography with tandem mass spectrometry detection. CYP3A5*3 and CYP3A5*6 genotype was determined using gel-electrophoresis or automated microfluidic electrophoresis. Neurotoxicity was determined by physical examination.

Results: The median age of children sampled was 6.5 years (range 1–16.25). Half the patients received concurrent corticosteroids for acute lymphoblastic leukaemia. Six patients (12%) had experienced grade 3 or 4 neurotoxicity. The median clearance, area under the curve and Cmax of vincristine was 482 mL/min/m2 (range 132–698), 49.7 mcg/L.h (16.5–143.1) and 3.5 mcg/L (1.0–31.2), respectively. In contrast to prediction, all but three children were homozygous for wild-type CYP3A5*3. No CYP3A5*6 polymorphisms were identified.

Conclusions: No correlation was identified between vincristine clearance, vincristine neurotoxicity, age, sex or concomitant steroid therapy. The limited sampling methodology proved acceptable to patients and families and would be suitable for larger scale studies including a wider range of genotypic variants and more detailed prospective evaluation of neurotoxicity.
Keyword CYP3A
Oncology
Pharmacogenetics
Pharmacology
Population
Pharmacokinetics
Vincristine
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 9 June 2011.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 22 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 29 Sep 2011, 01:38:25 EST by Charna Kovacevic on behalf of School of Pharmacy