Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia

Tristan M. Sissung; Klaus Mross; Seth M. Steinberg; Dirk Behringer; William D. Figg; Alex Sparreboom; Stephan Mielke

doi:10.1016/j.ejca.2006.06.017

Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia

Tristan M. Sissung, Klaus Mross, Seth M. Steinberg, Dirk Behringer, William D. Figg, Alex Sparreboom^*, Stephan Mielke

^*Corresponding author for this work

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

154 Scopus citations

Abstract

Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C > T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P = 0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P = 0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.

Original language	English
Pages (from-to)	2893-2896
Number of pages	4
Journal	European Journal of Cancer
Volume	42
Issue number	17
DOIs	https://doi.org/10.1016/j.ejca.2006.06.017
State	Published - Nov 2006
Externally published	Yes

Keywords

ABCB1
Neuropathy
Neutropenia
Paclitaxel
Polymorphisms

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title = "Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia",

abstract = "Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C > T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P = 0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P = 0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.",

keywords = "ABCB1, Neuropathy, Neutropenia, Paclitaxel, Polymorphisms",

author = "Sissung, {Tristan M.} and Klaus Mross and Steinberg, {Seth M.} and Dirk Behringer and Figg, {William D.} and Alex Sparreboom and Stephan Mielke",

note = "Funding Information: Patients with advanced solid tumours were treated with weekly, single-agent paclitaxel (Taxol), administered as a 1- or 3-h infusion. All patients provided written informed consent and the study was approved by the local ethics committee. Eligibility criteria, treatment schedules, and assessment of pharmacokinetic and toxicity profiles have been described previously. 8,9 The original clinical trial was supported by investigator-initiated grants from Bristol-Myers-Squibb, Munich, Germany. The current analysis was approved by the review board of the National Cancer Institute. Funding Information: This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA. ",

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AU - Figg, William D.

AU - Sparreboom, Alex

AU - Mielke, Stephan

N1 - Funding Information: Patients with advanced solid tumours were treated with weekly, single-agent paclitaxel (Taxol), administered as a 1- or 3-h infusion. All patients provided written informed consent and the study was approved by the local ethics committee. Eligibility criteria, treatment schedules, and assessment of pharmacokinetic and toxicity profiles have been described previously. 8,9 The original clinical trial was supported by investigator-initiated grants from Bristol-Myers-Squibb, Munich, Germany. The current analysis was approved by the review board of the National Cancer Institute. Funding Information: This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA.

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AB - Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C > T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P = 0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P = 0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.

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Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia

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Keywords

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