CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

Anne Joy M. De Graan; Laure Elens; Jason A. Sprowl; Alex Sparreboom; Lena E. Friberg; Bronno Van Der Holt; Pleun J. De Raaf; Peter De Bruijn; Frederike K. Engels; Ferry A.L.M. Eskens; Erik A.C. Wiemer; Jaap Verweij; Ron H.J. Mathijssen; Ron H.N. Van Schaik

doi:10.1158/1078-0432.CCR-12-3786

CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

Anne Joy M. De Graan
, Laure Elens
, Jason A. Sprowl
, Alex Sparreboom
, Lena E. Friberg
, Bronno Van Der Holt
, Pleun J. De Raaf
, Peter De Bruijn
, Frederike K. Engels
, Ferry A.L.M. Eskens
, Erik A.C. Wiemer
, Jaap Verweij
, Ron H.J. Mathijssen
, Ron H.N. Van Schaik

Pharmaceutical Sciences

Department of Medical Oncology
Erasmus University Rotterdam
St. Jude Children Research Hospital
Uppsala University
Department of Trials and Statistics

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel (_logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, C_max, or T _>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

Original language	English
Pages (from-to)	3316-3324
Number of pages	9
Journal	Clinical Cancer Research
Volume	19
Issue number	12
DOIs	https://doi.org/10.1158/1078-0432.CCR-12-3786
State	Published - Jun 15 2013

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De Graan, A. J. M., Elens, L., Sprowl, J. A., Sparreboom, A., Friberg, L. E., Van Der Holt, B., De Raaf, P. J., De Bruijn, P., Engels, F. K., Eskens, F. A. L. M., Wiemer, E. A. C., Verweij, J., Mathijssen, R. H. J., & Van Schaik, R. H. N. (2013). CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clinical Cancer Research, 19(12), 3316-3324. https://doi.org/10.1158/1078-0432.CCR-12-3786

@article{d0a36c1550774bc6bdeb9a442943f322,

title = "CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity",

abstract = "Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T >0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.",

author = "\{De Graan\}, \{Anne Joy M.\} and Laure Elens and Sprowl, \{Jason A.\} and Alex Sparreboom and Friberg, \{Lena E.\} and \{Van Der Holt\}, Bronno and \{De Raaf\}, \{Pleun J.\} and \{De Bruijn\}, Peter and Engels, \{Frederike K.\} and Eskens, \{Ferry A.L.M.\} and Wiemer, \{Erik A.C.\} and Jaap Verweij and Mathijssen, \{Ron H.J.\} and \{Van Schaik\}, \{Ron H.N.\}",

year = "2013",

month = jun,

day = "15",

doi = "10.1158/1078-0432.CCR-12-3786",

language = "English",

volume = "19",

pages = "3316--3324",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

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De Graan, AJM, Elens, L, Sprowl, JA, Sparreboom, A, Friberg, LE, Van Der Holt, B, De Raaf, PJ, De Bruijn, P, Engels, FK, Eskens, FALM, Wiemer, EAC, Verweij, J, Mathijssen, RHJ & Van Schaik, RHN 2013, 'CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity', Clinical Cancer Research, vol. 19, no. 12, pp. 3316-3324. https://doi.org/10.1158/1078-0432.CCR-12-3786

TY - JOUR

T1 - CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

AU - De Graan, Anne Joy M.

AU - Elens, Laure

AU - Sprowl, Jason A.

AU - Sparreboom, Alex

AU - Friberg, Lena E.

AU - Van Der Holt, Bronno

AU - De Raaf, Pleun J.

AU - De Bruijn, Peter

AU - Engels, Frederike K.

AU - Eskens, Ferry A.L.M.

AU - Wiemer, Erik A.C.

AU - Verweij, Jaap

AU - Mathijssen, Ron H.J.

AU - Van Schaik, Ron H.N.

PY - 2013/6/15

Y1 - 2013/6/15

N2 - Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T >0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

AB - Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T >0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

UR - https://www.scopus.com/pages/publications/84879474820

U2 - 10.1158/1078-0432.CCR-12-3786

DO - 10.1158/1078-0432.CCR-12-3786

M3 - Article

C2 - 23640974

AN - SCOPUS:84879474820

SN - 1078-0432

VL - 19

SP - 3316

EP - 3324

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 12

ER -

CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity

Abstract

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