Sorafenib exposure decreases over time in patients with hepatocellular carcinoma.
BACKGROUND
Intra-patient variability in sorafenib pharmacokinetics has been poorly investigated to date. We hypothesized that sorafenib clearance could decrease over time, as seen with imatinib.


METHODS
Sorafenib plasma concentrations were determined by liquid chromatography, every 2 weeks, in consecutive hepatocellular carcinoma patients treated with sorafenib. Sorafenib dose-normalized area under the concentration-time curve (AUC) was determined from a population pharmacokinetics model, and its kinetics was analyzed in order to identify possible alterations of exposure over time.


RESULTS
Fifteen hepatocellular carcinoma patients with Child-Pugh A cirrhosis, in whom sorafenib dosing remained unchanged from initiation of treatment to disease progression, were eligible for this analysis. Sorafenib AUC significantly decreased over time: the median AUC during the third month of treatment was lower than that observed after one month of treatment (43.0 vs. 60.3 mg/L.h, p = 0.008). Most importantly, median sorafenib AUC at the time of progression was almost two-fold lower than that observed after one month of therapy (33.2 vs. 60.3 mg/L.h, p = 0.007). These findings suggest an induction of expression of efflux transporters in the gut wall, or an induction of sorafenib metabolism.


CONCLUSIONS
In patients with progressive disease in whom exposure markedly decreased from baseline, sorafenib dose escalation could be considered, aiming to restore an adequate drug exposure and possibly anti-tumor activity.
CERIA (Centre for Research on Angiogenesis Inhibitors), Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, 27, rue du faubourg Saint Jacques, F75014, Paris, France.
Jennifer
J
Arrondeau
Olivier
O
Mir
Pascaline
P
Boudou-Rouquette
Romain
R
Coriat
Stanislas
S
Ropert
Guillaume
G
Dumas
Manuel J
MJ
Rodrigues
Benoit
B
Rousseau
Benoit
B
Blanchet
François
F
Goldwasser
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077157:Sorafenib
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib