DDMODEL00000049: TDM1_Antibody_Drug_Conjugate_PK_Model

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Model Description: Multicompartment PK model describing total antibody and drug:antibody ratio concentrations from cynomolgus monkey data
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  • A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for treatment of metastatic breast cancer.
  • Bender B, Leipold DD, Xu K, Shen BQ, Tibbitts J, Friberg LE
  • The AAPS journal, 9/2014, Volume 16, Issue 5, pages: 994-1008
  • Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA, brendan.bender@farmbio.uu.se.
  • Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n?=?34) and cynomolgus monkeys (n?=?18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are ?3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints.
Brendan Bender
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  • Model owner: Brendan Bender
  • Submitted: Dec 17, 2015 11:44:38 AM
  • Last Modified: Dec 17, 2015 11:44:38 AM
  • Version: 15 public model Download this version
    • Submitted on: Dec 17, 2015 11:44:38 AM
    • Submitted by: Brendan Bender
    • With comment: Edited model metadata online.