Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with
- PDF / 1,386,358 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 93 Downloads / 143 Views
ORIGINAL PAPER
Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1 Alison Betts1,4,8 • Tracey Clark2 • Paul Jasper3 • John Tolsma3 • Piet H. van der Graaf4 • Edmund I. Graziani5 • Edward Rosfjord6 • Matthew Sung6 • Dangshe Ma7 • Frank Barletta6,9 Received: 13 December 2019 / Accepted: 7 July 2020 Ó The Author(s) 2020
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 lg/mL (n = 7) for PF-06804103 and from 4.7 to 29 lg/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. Keywords HER2 Antibody drug conjugate Translational modeling Tumor static concentration Pharmacokinetics PK/PD Oncology
Introduction Human epidermal growth factor receptor 2 (HER2) overexpression in cancer patients is a genetic alteration that promotes cancer cell proliferation and survival, resulting in increased tumor growth and poor clinical outcome in the absence of HER2 targeted therapy [1, 2]. HER2? cancers account for approximately 20% of all breast cancers [1, 2]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09702-3) contains supplementary material, which is available to authorized users. & Alison Betts [email protected] & Frank Barletta [email protected] Extended author information available on the last page of the article
Trastuzumab, a monoclonal antibody (mAb) which specifically targets HER2, has revolutionized treatment as one of the first non-hormonal medicines for breast cancer [3]. ADCs are a targeted therapy for cancer treatment, combining a specific mAb to a tumor antigen linked to a potent cytotoxic agent [4]. The aim for this type of therapeutic is to target the cytotoxic drug to tumor cells, thus maximizing efficacy while min
Data Loading...
