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

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.