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Sökning: WFRF:(Mathijssen Ron H. J.) > CYP3A4*22 Genotype ...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003560naa a2200409 4500
001oai:DiVA.org:uu-204106
003SwePub
008130722s2013 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2041062 URI
0247 a https://doi.org/10.1158/1078-0432.CCR-12-37862 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a de Graan, Anne-Joy M.4 aut
2451 0a CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
264 1c 2013
338 a print2 rdacarrier
520 a 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 ((log)AUC) 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.
7001 a Elens, Laure4 aut
7001 a Sprowl, Jason A.4 aut
7001 a Sparreboom, Alex4 aut
7001 a Friberg, Lena E.u Uppsala universitet,Institutionen för farmaceutisk biovetenskap4 aut0 (Swepub:uu)lenasimo
7001 a van der Holt, Bronno4 aut
7001 a de Raaf, Pleun J.4 aut
7001 a de Bruijn, Peter4 aut
7001 a Engels, Frederike K.4 aut
7001 a Eskens, Ferry A. L. M.4 aut
7001 a Wiemer, Erik A. C.4 aut
7001 a Verweij, Jaap4 aut
7001 a Mathijssen, Ron H. J.4 aut
7001 a van Schaik, Ron H. N.4 aut
7102 a Uppsala universitetb Institutionen för farmaceutisk biovetenskap4 org
7730 t Clinical Cancer Researchg 19:12, s. 3316-3324q 19:12<3316-3324x 1078-0432x 1557-3265
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-204106
8564 8u https://doi.org/10.1158/1078-0432.CCR-12-3786

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