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2015 ; 106
(5
): 611-7
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Phase I study of tivantinib in Japanese patients with advanced hepatocellular
carcinoma: Distinctive pharmacokinetic profiles from other solid tumors
#MMPMID25711511
Okusaka T
; Aramaki T
; Inaba Y
; Nakamura S
; Morimoto M
; Moriguchi M
; Sato T
; Ikawa Y
; Ikeda M
; Furuse J
Cancer Sci
2015[May]; 106
(5
): 611-7
PMID25711511
show ga
A c-Met inhibitor tivantinib is a candidate anticancer agent for patients with
hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for
tivantinib. Previous Japanese phase I studies in patients with solid tumors
(except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19
extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this
study, Japanese patients with HCC in whom sorafenib treatment has failed were
enrolled to evaluate the safety, tolerability and pharmacokinetics of oral
tivantinib as a single agent. The dose was escalated separately in EM and PM,
from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total
of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID,
dose-limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6)
and 7 PM (capsule: 4, tablet: 3) during the DLT-observation period (for 29 days
after first dosing). At this dose, the pharmacokinetic profiles of tivantinib
(AUC0-12 and Cmax ) did not remarkably differ between EM and PM. When treated
with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed
neutropenia-related DLT accompanying plasma tivantinib concentration higher than
expected from the previous studies. Consequently, PM did not receive 240 mg BID.
In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients
with HCC regardless of CYP2C19 phenotype.
|Administration, Oral
[MESH]
|Aged
[MESH]
|Antineoplastic Agents/pharmacokinetics/therapeutic use
[MESH]
free
free
free
