SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

A. Khatri, B. W. Williams, James Fisher, Richard Brundage, V. J. Gurvich, Lev G Lis, Keith M Skubitz, Arkadiusz Z Dudek, Edward W Greeno, Robert A Kratzke, J. K. Lamba, Mark N Kirstein

Research output: Contribution to journalArticle

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Abstract

Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m-2 min-1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m-2 min-1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

Original languageEnglish (US)
Pages (from-to)304-312
Number of pages9
JournalBritish Journal of Cancer
Volume110
Issue number2
DOIs
StatePublished - Jan 21 2014

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gemcitabine
Pharmacokinetics
Genotype
Neoplasms
Cytidine Deaminase
Body Surface Area
Blood Cells
Creatinine
Therapeutics
Alleles

Keywords

  • covariates
  • dFdCTP
  • gemcitabine
  • infusion rate
  • pharmacogenomics
  • population pharmacokinetic model

Cite this

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours. / Khatri, A.; Williams, B. W.; Fisher, James; Brundage, Richard; Gurvich, V. J.; Lis, Lev G; Skubitz, Keith M; Dudek, Arkadiusz Z; Greeno, Edward W; Kratzke, Robert A; Lamba, J. K.; Kirstein, Mark N.

In: British Journal of Cancer, Vol. 110, No. 2, 21.01.2014, p. 304-312.

Research output: Contribution to journalArticle

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abstract = "Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m-2 min-1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m-2 min-1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.",
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T1 - SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

AU - Khatri, A.

AU - Williams, B. W.

AU - Fisher, James

AU - Brundage, Richard

AU - Gurvich, V. J.

AU - Lis, Lev G

AU - Skubitz, Keith M

AU - Dudek, Arkadiusz Z

AU - Greeno, Edward W

AU - Kratzke, Robert A

AU - Lamba, J. K.

AU - Kirstein, Mark N

PY - 2014/1/21

Y1 - 2014/1/21

N2 - Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m-2 min-1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m-2 min-1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

AB - Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m-2 min-1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m-2 min-1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

KW - covariates

KW - dFdCTP

KW - gemcitabine

KW - infusion rate

KW - pharmacogenomics

KW - population pharmacokinetic model

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JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

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