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Eur J Cancer. 2016 Mar;55:56-64. doi: 10.1016/j.ejca.2015.12.007. Epub 2016 Jan 12.

Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma.

Author information

1
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: G.J.Veal@ncl.ac.uk.
2
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom.
3
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Tata Memorial Hospital, Mumbai, India.
4
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
5
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.

Abstract

INTRODUCTION:

Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology.

METHODS:

A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤ 18 years receiving cyclophosphamide (250 mg/m(2)), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed.

RESULTS:

A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m(2), respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m(2) versus 2.20 ± 0.31 L/h/m(2), P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m(2) versus 4.35 ± 0.37 L/h/m(2), P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival.

CONCLUSION:

The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome.

KEYWORDS:

B-cell NHL; Chemotherapy; Cyclophosphamide; Paediatrics; Pharmacogenetics; Pharmacokinetics

PMID:
26773420
PMCID:
PMC4778608
DOI:
10.1016/j.ejca.2015.12.007
[Indexed for MEDLINE]
Free PMC Article

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