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01-08-2015 | PHASE I STUDIES

Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT)

Authors: Joanne W. Chiu, Kelvin Chan, Eric X. Chen, Lillian L. Siu, Albiruni R. Abdul Razak

Published in: Investigational New Drugs | Issue 4/2015

Summary

Background Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided). Methods Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. Results Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t_1/2 of 58 h, C_max of 17 ng/ml, T_max of 8 h, AUC_0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. Conclusion Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in C_max and 33–44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.

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Title: Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT)
Authors: Joanne W. Chiu
Kelvin Chan
Eric X. Chen
Lillian L. Siu
Albiruni R. Abdul Razak
Publication date: 01-08-2015
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2015
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-015-0245-3

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