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Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In oncology, there is a need to optimize drug treatment for efficient eradication of tumors, minimization of adverse effects (AEs), and prolonging patient survival. Pharmacometric models can be developed to streamline information between drug development phases, describe and quantify response to treatment, and determine dose regimens that balance toxicity and efficacy. In this thesis, data from trastuzumab emtansine (T-DM1) and taxane drug treatment were used to develop pharmacometric models of pharmacokinetics (PK), AEs, anti-tumor response, and survival, supporting drug development.

T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex distribution of T-DM1 was elucidated through PK models developed using in vitro and in vivo rat and cynomolgus monkey DAR data. Mechanism–based PK/pharmacodynamic (PKPD) models were also developed for T-DM1 that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. Variable patterns of platelet and transaminase (ALT and AST) response were quantified, including an effect of Asian ethnicity that was related to higher incidences of TCP.  Model simulations, comparing dose intensities (DI) and Grade 3/4 incidences between the approved T-DM1 dose (3.6 mg/kg every three weeks) and weekly regimens, determined that 2.4 mg/kg weekly provided the highest DI.

Docetaxel and paclitaxel are taxane treatment options for HER2–negative breast cancer. Tumor response data from these treatments were used to develop a mechanism–based model of tumor quiescence and drug–resistance. Subsequently, a parametric survival analysis found that tumor baseline and the model–predicted time to tumor growth (TTG) were predictors of overall survival (OS). This tumor and OS modeling approach can be applied to other anticancer treatments with similar patterns of drug–resistance.

Overall, the pharmacometric models developed within this thesis present new modeling approaches and provide understanding on ADC PK and PKPD (TCP and hepatotoxicity), as well as drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards dose finding for anticancer drugs in development, especially ADCs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 217
Keyword [en]
pharmacometric, PKPD, model, breast cancer, T-DM1, thrombocytopenia, hepatotoxiticy, HER2
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-292617ISBN: 978-91-554-9603-6 (print)OAI: oai:DiVA.org:uu-292617DiVA: diva2:926532
Public defence
2016-09-02, B/B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-06-03 Created: 2016-05-04 Last updated: 2016-06-22Bibliographically approved
List of papers
1. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
Open this publication in new window or tab >>A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
Show others...
2012 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 70, no 4, 591-601 p.Article in journal (Refereed) Published
Abstract [en]

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEMA (R) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. The model described the platelet data well and predicted the incidence of grade a parts per thousand yen3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the similar to 8 % incidence of grade a parts per thousand yen3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.

Keyword
Trastuzumab emtansine, T-DM1, Thrombocytopenia, Population pharmacokinetic/pharmacodynamic model, Semimechanistic, Cumulative TCP
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183550 (URN)10.1007/s00280-012-1934-7 (DOI)000309201500013 ()
Available from: 2012-12-07 Created: 2012-10-29 Last updated: 2017-09-11Bibliographically approved
2. An integrated pharmacokinetic-pharmacodynamic (PKPD) modeling analysis of trastuzumab emtansine (T-DM1)-induced thrombocytopenia (TCP) and hepatotoxicity in patients with HER2–positive metastatic breast cancer
Open this publication in new window or tab >>An integrated pharmacokinetic-pharmacodynamic (PKPD) modeling analysis of trastuzumab emtansine (T-DM1)-induced thrombocytopenia (TCP) and hepatotoxicity in patients with HER2–positive metastatic breast cancer
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
Pharmacodynamic, PKPD, Trastuzumab emtansine, T-DM1, Breast Cancer, Thrombocytopenia, Hepatotoxicity, HER2, Dose intensity
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-292736 (URN)
Available from: 2016-05-09 Created: 2016-05-09 Last updated: 2016-06-22
3. A Mechanistic Pharmacokinetic Model Elucidating the Disposition of Trastuzumab Emtansine (T-DM1), an Antibody-Drug Conjugate (ADC) for Treatment of Metastatic Breast Cancer
Open this publication in new window or tab >>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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2014 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 16, no 5, 994-1008 p.Article in journal (Refereed) Published
Abstract [en]

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 a parts per thousand yen3 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.

Keyword
antibody-drug conjugate, deconjugation, population pharmacokinetic model, T-DM1, trastuzumab emtansine
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-235072 (URN)10.1208/s12248-014-9618-3 (DOI)000341434100011 ()24917179 (PubMedID)
Available from: 2014-10-29 Created: 2014-10-28 Last updated: 2017-12-05Bibliographically approved
4. A mechanism-based model of tumor quiescence and drug-resistance in HER2–negative metastatic breast cancer patients receiving docetaxel or paclitaxel
Open this publication in new window or tab >>A mechanism-based model of tumor quiescence and drug-resistance in HER2–negative metastatic breast cancer patients receiving docetaxel or paclitaxel
(English)Manuscript (preprint) (Other academic)
Keyword
tumor quiescense, drug resistance, model, HER2, breast cancer
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-292728 (URN)
Available from: 2016-05-08 Created: 2016-05-08 Last updated: 2016-06-22

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