Pan-Her不可逆抑制剂NOV120101 (Poziotinib)(HM781-36B)

Patent application title: NOVEL AMIDE DERIVATIVE FOR INHIBITING THE GROWTH OF CANCER CELLS
http://www.faqs.org/patents/app/20100179120
Publication date: 2010-07-15
Patent application number: 20100179120

Title: Population Pharmacokinetic Analysis of a novel pan-HER inhibitor, HM781-36B, in Patients with Advanced Malignant Solid Tumors
Authors: Yook-Hwan Noh* (1), Hyeong-Seok Lim (1), Kyun-Seop Bae (1)
Institutions: (1) Ulsan University College of Medicine, Asan Medical Center, Seoul, Korea
Objectives: HM781-36B is an orally active inhibitor of human epidermal growth factor receptors HER1, HER2, and HER4 tyrosine kinase. The objectives of this work were to quantitatively describe the pharmacokinetic (PK) characteristics of HM781-36 in Phase I oncology patients and to evaluate the potential sources of its PK variability.
Methods: The HM781-36 population PK analysis were performed using the data from three phase I clinical studies, which included 1933 HM781-36 plasma concentrations from 58 patients with advanced solid cancers (101 PK study: 39 patients, 102 PK study: 11 patients, 102 food effect PK study: 8). In 101 PK study, HM781-36B was administered once-daily oral doses ranged from 0.5 to 32 mg (0.5, 1, 2, 4, 8, 12, 16, 20, 24 and 32 mg/day) and were given for 14 days. Blood samples for PK were collected up to 24 hr on the first dosing day and up to 48 hr after the last dosing. In 102 PK and 102 food-effect studies, HM781-36B was administered with once-daily oral doses ranged from 12 to 24 mg (food effect study – 16 mg only) and was given for 28 days. Blood samples for PK were collected up to 24 hr on the first and last dosing day. Plasma HM781-36 concentrations were analyzed using liquid chromatography-mass spectrometry. PK analyses were performed by non-compartment method, as well as compartmental method. Nonlinear mixed effects modeling for the population pharmacokinetic analysis of HM781-36 was performed using NONMEM version 7.2 with ADVAN2 subroutine and a combined exponential and additive error model to estimate the residual unexplained error. The model selection was based on the generated objective function value (OFV) and diagnostic plots. The robustness of the final model was evaluated using a bootstrap procedure and model stability and appropriateness using numerical and visual predictive checks.
Results: A one-compartment model with first order absorption and mixed residual error model best described the pharmacokinetic data. The final base model predicted a population apparent clearance (CL/F) of HM781-36 of 16.74 L/hr. The absorption rate constant, central volume of distribution, and apparent clearance were 1.69 hr-1 (between-subject variability, BSV: 10.7%), 120 L (BSV: 4.8%), and 16.7 L/hr (BSV: 4.3%), respectively. The model fitted well with the observed data, and the bootstrap and predictive checks guaranteed robustness and appropriateness of the population pharmacokinetic model. No significant relationship was observed between PK parameters and patient demographics.
Conclusions: A population pharmacokinetic model for HM781-36 in patients with advanced malignant solid tumors has been developed. This model will be used as HM781-36 basic drug model for dose individualization and adjustment and for designing later Phase II and III clinical trials. This study provided a rationale for further clinical evaluation of HM781-36B.
References:
[1] JaeWoo Kim, Kyun-Seop Bae. Pharmacokinetics of the pan-HER inhibitor, HM781-36B, in patients with advanced malignant solid tumors (Abstract), JSCPT-KSCPT-ASCPT Joint conference 2011 and the 32nd JSCPT Annual Scientific meeting.

期待中，感谢老马！

谢谢老马哥的又一个新消息！

   感谢马哥！对易，特耐药后的治疗781和4002哪个更好一些呢或者有效率更高一些？

   有没有高人能解答一下。

感谢老马！感谢老马！

老马总是给我们带来新的希望，不知现在这个药的进展到了什么阶段了，有病友开始试用了么？期盼有新的消息

论坛有人已经在使用了 。

有用的么？效果如何啊？

肝癌能用吗？