当前位置： SCI文献检索 > JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS期刊下所有文献 > Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1.

Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1.

Abstract：

:A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PF-06804103 and T-DM1 was determined across a range of mouse tumor xenograft models, using a tumor growth inhibition model. The tumor static concentration was assigned as the minimal efficacious concentration. PF-06804103 was concluded to be more potent than T-DM1 across cell lines studied. TSCs ranged from 1.0 to 9.8 µg/mL (n = 7) for PF-06804103 and from 4.7 to 29 µg/mL (n = 5) for T-DM1. Two experimental models which were resistant to T-DM1, responded to PF-06804103 treatment. A mechanism-based target mediated drug disposition (TMDD) model was used to predict the human PK of PF-06804103. This model was constructed and validated based on T-DM1 which has non-linear PK at doses administered in the clinic, driven by binding to shed HER2. Non-linear PK is predicted for PF-06804103 in the clinic and is dependent upon circulating HER2 extracellular domain (ECD) concentrations. The models were translated to human and suggested greater efficacy for PF-06804103 compared to T-DM1. In conclusion, a fit-for-purpose translational PK/PD strategy for ADCs is presented and used to compare a new generation HER2 ADC with T-DM1.

journal_name

J Pharmacokinet Pharmacodyn

journal_title

Journal of pharmacokinetics and pharmacodynamics

authors

Betts A,Clark T,Jasper P,Tolsma J,van der Graaf PH,Graziani EI,Rosfjord E,Sung M,Ma D,Barletta F

doi

10.1007/s10928-020-09702-3

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

513-526

issue

5

eissn

1567-567X

issn

1573-8744

pii

10.1007/s10928-020-09702-3

journal_volume

47

pub_type

杂志文章

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