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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

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Abstract

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.

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Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA

    Brendan Bender

  2. UCB Celltech, Berkshire, UK

    Jay Tibbitts

  3. Department of Pharmacodynamics and Pharmacokinetics, Genentech Inc., South San Francisco, California, USA

    Douglas D. Leipold & Ben-Quan Shen

  4. Department of Bioanalytical Research and Development, Genentech Inc., South San Francisco, California, USA

    Keyang Xu

  5. Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, Uppsala, 75124, Sweden

    Brendan Bender & Lena E. Friberg

Authors
  1. Brendan Bender
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  2. Douglas D. Leipold
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  3. Keyang Xu
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  4. Ben-Quan Shen
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  5. Jay Tibbitts
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  6. Lena E. Friberg
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Corresponding author

Correspondence to Brendan Bender.

Additional information

Jay Tibbitts and Lena E. Friberg contributed equally to this work.

Appendices

Appendix 1: Calculation of exposure (AUC) for T-DM1 and its individual DAR moieties

As illustrated in Fig. 1a, each DAR moiety is eliminated from its respective compartment via two rates: (1) deconjugation to the next DAR moiety, and (2) antibody clearance mechanisms. In order to derive the equations for the individual DAR exposures (i.e., AUCDAR0–AUCDAR7) and T-DM1 exposure (i.e., the sum of AUCDAR1–AUCDAR7), we define the following:

  1. 1.

    Dose = T-DM1 dose (mg/kg) × weight (kg)

  2. 2.

    fnn = fraction of DAR moiety (n) in the T-DM1DAR 3.1 dose product; e.g., fn7 = 0.02 (See Methods: Preparation of T-DM1DAR 3.1 and T-DM1DAR 1.5 Dose Products)

  3. 3.

    k TT = rate constant for antibody clearance mechanisms = (CLTT/V1); e.g., k TT = 17.4/148 = 0.118 day−1; Table II, cynomolgus monkeys

  4. 4.

    k n,TOT = total elimination rate for each DAR moiety (n) = (k n → n − 1 + kTT); e.g., k 7,TOT = k 7 → 6 + k TT = 0.341 + 0.118 = 0.459 day−1; Table II, cynomolgus monkeys

The system of T-DM1 deconjugation is a catenary chain containing the moieties DAR0–DAR7. Not only does the exposure of each moiety derive from its initial percentage in the dose product but also from input from higher DAR species. The fraction of each DAR moiety serving as input into the other compartments is calculated as follows:

  • F n → n − 1 = fraction of DAR moiety (n) as input to next DAR (n − 1) compartment = (k n → n − 1/(k n → n − 1 + k TT)); e.g., F 7 → 6 = (k 7 → 6/(k 7 → 6 + k TT)) = (0.341/(0.341 + 0.118)) = 0.742; Table II, cynomolgus monkeys

  • The fraction of DAR moiety as input to all DAR compartments is as follows, using DAR7 as an example:

    1. 1.

      F 7 → 6 = the fraction of DAR7 as input to DAR6

    2. 2.

      F 7 → 5 = F 7 → 6 × F 6 → 5; the fraction of DAR7 as input to DAR5

    3. 3.

      F 7 → 4 = F 7 → 6 × F 6 → 5 × F 5 → 4; the fraction of DAR7 as input to DAR4

    4. 4.

      F 7 → 3 = F 7 → 6 × F 6 → 5 × F 5 → 4 × F 4 → 3; the fraction of DAR7 as input to DAR3

    5. 5.

      F 7 → 2 = F 7 → 6 × F 6 → 5 × F 5 → 4 × F 4 → 3 × F 3 → 2; the fraction of DAR7 as input to DAR2

    6. 6.

      F 7 → 1 = F 7 → 6 × F 6 → 5 × F 5 → 4 × F 4 → 3 × F 3 → 2 × F 2 → 1; the fraction of DAR7 as input to DAR1

    7. 7.

      F 7 → 0 = F 7 → 6 × F 6 → 5 × F 5 → 4 × F 4 → 3 × F 3 → 2 × F 2 → 1 × F 1 → 0; the fraction of DAR7 as input to DAR0

Equations for the AUC of the individual DAR0–DAR7 moieties are shown below. Here, the total amount of each DAR, deriving from its percentage in the dose product and from input from the higher DAR moieties, is divided by its respective clearance to yield AUC.

  1. 1.

    AUCDAR7 = Dose × fn7/(V 1 × k 7,TOT)

  2. 2.

    AUCDAR6 = dose × (F 7 → 6 × fn7 + fn6)/(V 1 × k6,TOT)

  3. 3.

    AUCDAR5 = Dose × (F7 → 5 × fn7 + F6 → 5 × fn6 + fn5)/(V 1 × k 5,TOT)

  4. 4.

    AUCDAR4 = dose × (F 7 → 4 × fn7 + F 6 → 4 × fn6 + F 5 → 4 × fn5 + fn4)/(V 1 × k 4,TOT)

  5. 5.

    AUCDAR3 = dose × (F 7 → 3 × fn7 + F 6 → 3 × fn6 + F 5 → 3 × fn5 + F 4 → 3 × fn4 + fn3)/(V 1 × k 3,TOT)

  6. 6.

    AUCDAR2 = dose × (F 7 → 2 × fn7 + F 6 → 2 × fn6 + F 5 → 2 × fn5 + F 4 → 2 × fn4 + F 3 → 2 × fn3 + fn2)/(V 1 × k 2,TOT

  7. 7.

    AUCDAR1 = dose × (F 7 → 1 × fn7 + F 6 → 1 × fn6 + F 5 → 1 × fn5 + F 4 → 1 × fn4 + F 3 → 1 × fn3 + F 2 → 1 × fn2 + fn1)/(V 1 × k 1,TOT)

  8. 8.

    AUCDAR0 = dose × (F 7 → 0 × fn7 + F 6 → 0 × fn6 + F 5 → 0 × fn5 + F 4 → 0 × fn4 + F 3 → 0 × fn3 + F 2 → 0 × fn2 + F 1 → 0 × fn1 + fn0)/(V 1 × k TT)

The overall T-DM1 exposure is the sum of the individual DAR1–DAR7 AUCs.

  1. 1.

    AUCTDM1 = AUC DAR7 + AUCDAR6 + AUCDAR5 + AUCDAR3 + AUC DAR2 + AUCDAR1, thus

    AUCTDM1 = dose × fn7/(V 1 × k 7,TOT) + dose × (F 7 → 6 × fn7 + fn6)/(V 1 × k 6,TOT) + …etc.

  2. 2.

    Substitution, in the above equation, with the Table II parameter values for cynomolgus monkeys and the fn1–fn7 values for the T-DM1DAR 3.1 dose product (see “Preparation of T-DM1DAR 3.1 and T-DM1DAR 1.5 Dose Products”) yields:

    • T-DM1DAR 3.1 dose product at 3.6 mg/kg has an AUCTDM1 = 538 μg/mL × day−1

Appendix 2: Dose calculations (mg/kg) for T-DM1 dose products targeting a specified T-DM1 AUC

Appendix 1 derived the mathematical equations for T-DM1 AUC and its individual DAR AUCs. From these equations, the dose (mg/kg) of the T-DM1DAR 1.5 dose product equivalent to 3.6 mg/kg T-DM1DAR 3.1 by AUC is calculated here.

  1. 1.

    From Appendix 1:

    • T-DM1DAR 3.1 dose product at 3.6 mg/kg has an AUCTDM1 = 538 μg/mL × day−1

    • AUCTDM1 = dose × fn7/(V 1 × k 7,TOT) + dose × (F 7 → 6 × fn7 + fn6)/(V 1 × k 6,TOT) + … etc.

  2. 2.

    Rearrangement yields:

    • Dose = AUCTDM1/(fn7/(V 1 × k 7,TOT) + (F 7 → 6 × fn7 + fn6)/(V 1 × k 6,TOT) + … etc.)

  3. 3.

    Substitution, in the above equation with the Table II parameter values for cynomolgus monkeys, and the appropriate fn1–fn7 values for the T-DM1DAR 1.5 dose product (see “Preparation of T-DM1DAR 3.1 and T-DM1DAR 1.5 Dose Products”) yields:

    • T-DM1DAR 1.5 dose product at 5.16 mg/kg has an AUCTDM1 = 538 μg/mL × day−1

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Bender, B., Leipold, D.D., Xu, K. et al. A Mechanistic Pharmacokinetic Model Elucidating the Disposition of Trastuzumab Emtansine (T-DM1), an Antibody–Drug Conjugate (ADC) for Treatment of Metastatic Breast Cancer. AAPS J 16, 994–1008 (2014). https://doi.org/10.1208/s12248-014-9618-3

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