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Pharmacokinetics and pharmacogenetics of sorafenib in patients with hepatocellular carcinoma: Implications for combination trials
Author(s) -
DíazGonzález Álvaro,
Sapena Víctor,
Boix Loreto,
Brunet Mercè,
Torres Ferrán,
LLarch Neus,
Samper Esther,
Millán Olga,
Corominas Josep,
Iserte Gemma,
SanduzziZamparelli Marco,
da Fonseca Leonardo G.,
Darnell Anna,
Belmonte Ernest,
Forner Alejandro,
Ayuso Carmen,
Bruix Jordi,
Reig María
Publication year - 2020
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14587
Subject(s) - sorafenib , pharmacokinetics , medicine , hepatocellular carcinoma , pharmacology , lenvatinib , adverse effect , oncology , pharmacogenetics , cmax , cyp2c19 , metabolite , gastroenterology , genotype , biology , cytochrome p450 , metabolism , biochemistry , gene
Abstract Background & Aims Sorafenib and lenvatinib are the first‐line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. Methods We assessed the pharmacokinetics of sorafenib and its N‐oxide metabolite at day‐0, day‐7, day‐30, day‐60, day‐90, day‐120, day‐150 and day‐180 and nine single‐nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. Results We prospectively included 49 patients (96% cirrhotic, 37% hepatitis‐C, 82% Child‐Pugh‐A and 59% BCLC‐C). Pharmacokinetic values peaked at day‐7 and progressively declined until day‐60. In the 16 patients without further dose modifications after day‐60, pharmacokinetic values remained stable through day‐180 (sorafenib P = .90; N‐oxide P = .93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N‐oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972 . Conclusions Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.