TY - JOUR
T1 - Pharmacokinetics and pharmacogenetics of sorafenib in patients with hepatocellular carcinoma
T2 - Implications for combination trials
AU - Díaz-González, Álvaro
AU - Sapena, Víctor
AU - Boix, Loreto
AU - Brunet, Mercè
AU - Torres, Ferrán
AU - LLarch, Neus
AU - Samper, Esther
AU - Millán, Olga
AU - Corominas, Josep
AU - Iserte, Gemma
AU - Sanduzzi-Zamparelli, Marco
AU - da Fonseca, Leonardo G.
AU - Darnell, Anna
AU - Belmonte, Ernest
AU - Forner, Alejandro
AU - Ayuso, Carmen
AU - Bruix, Jordi
AU - Reig, María
N1 - © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2020/7/25
Y1 - 2020/7/25
N2 - 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.
AB - 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.
KW - hepatocellular carcinoma
KW - outcome
KW - pharmacokinetics
KW - safety
KW - sorafenib
KW - Tyrosine Kinase Inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85088370181&partnerID=8YFLogxK
U2 - 10.1111/liv.14587
DO - 10.1111/liv.14587
M3 - Artículo
C2 - 33021346
AN - SCOPUS:85088370181
VL - 40
SP - 2476
EP - 2488
IS - 10
ER -