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Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake.
Pharmacogenomics. 2020 Feb; 21(3):173-179.P

Abstract

A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (UGT1A9-rs3832043) and nuclear receptor PXR (NR1I2-rs3814055, NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.

Authors+Show Affiliations

SMARTc Unit, CRCM, Inserm U1068, Aix Marseille University, Marseille, France.Clinical Biochemistry Department, Caremeau University Hospital of Nîmes, Nîmes, France.SMARTc Unit, CRCM, Inserm U1068, Aix Marseille University, Marseille, France.Clinical Biochemistry Department, Caremeau University Hospital of Nîmes, Nîmes, France.SMARTc Unit, CRCM, Inserm U1068, Aix Marseille University, Marseille, France.Biologie du Médicament - Toxicologie, Hôpital Cochin, AP-HP, Paris, France.SMARTc Unit, CRCM, Inserm U1068, Aix Marseille University, Marseille, France.Medical Oncology Unit, La Timone University Hospital of Marseille Assistance Publique Hôpitaux de Marseille, Marseille, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31967518

Citation

Ba, Hai le, et al. "Pharmacogenetics and Pharmacokinetics Modeling of Unexpected and Extremely Severe Toxicities After Sorafenib Intake." Pharmacogenomics, vol. 21, no. 3, 2020, pp. 173-179.
Ba HL, Mbatchi L, Gattacceca F, et al. Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake. Pharmacogenomics. 2020;21(3):173-179.
Ba, H. L., Mbatchi, L., Gattacceca, F., Evrard, A., Lacarelle, B., Blanchet, B., Ciccolini, J., & Salas, S. (2020). Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake. Pharmacogenomics, 21(3), 173-179. https://doi.org/10.2217/pgs-2019-0127
Ba HL, et al. Pharmacogenetics and Pharmacokinetics Modeling of Unexpected and Extremely Severe Toxicities After Sorafenib Intake. Pharmacogenomics. 2020;21(3):173-179. PubMed PMID: 31967518.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake. AU - Ba,Hai le, AU - Mbatchi,Litaty, AU - Gattacceca,Florence, AU - Evrard,Alexandre, AU - Lacarelle,Bruno, AU - Blanchet,Benoit, AU - Ciccolini,Joseph, AU - Salas,Sébastien, PY - 2020/1/23/entrez KW - pharmacogenetics KW - pharmacokinetics KW - sorafenib KW - therapeutic drug monitoring KW - toxicity SP - 173 EP - 179 JF - Pharmacogenomics JO - Pharmacogenomics VL - 21 IS - 3 N2 - A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (UGT1A9-rs3832043) and nuclear receptor PXR (NR1I2-rs3814055, NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake. SN - 1744-8042 UR - https://www.unboundmedicine.com/medline/citation/31967518/Pharmacogenetics_and_pharmacokinetics_modeling_of_unexpected_and_extremely_severe_toxicities_after_sorafenib_intake L2 - http://www.futuremedicine.com/doi/full/10.2217/pgs-2019-0127?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
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