Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake

• Published in: Pharmacogenomics 2020-02, Vol.21 (3), p.173-179
• Main Authors: Ba, Hai le, Mbatchi, Litaty, Gattacceca, Florence, Evrard, Alexandre, Lacarelle, Bruno, Blanchet, Benoit, Ciccolini, Joseph, Salas, Sébastien
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Antineoplastic Agents - blood; Antineoplastic Agents - toxicity; Area Under Curve; Biochemistry; Biochemistry, Molecular Biology; Cancer; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Humans; Life Sciences; Liver; Liver - drug effects; Liver - enzymology; Middle Aged; Pharmaceutical sciences; pharmacogenetics; Pharmacogenomic Testing; pharmacokinetics; Polymorphism, Single Nucleotide; Pregnane X Receptor; Pregnane X Receptor - genetics; Severity of Illness Index; Sorafenib; Sorafenib - blood; Sorafenib - toxicity; therapeutic drug monitoring; Thyroid Cancer, Papillary; Thyroid Cancer, Papillary - blood; Thyroid Cancer, Papillary - drug therapy; Thyroid Neoplasms; Thyroid Neoplasms - blood; Thyroid Neoplasms - drug therapy; toxicity
• ISSN: 1462-2416; 1744-8042
• DOI: 10.2217/pgs-2019-0127

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 ( -rs3832043) and nuclear receptor PXR ( -rs3814055 -rs2472677 and -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 , genetic polymorphisms of have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.