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Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer

Författare

Uppsala universitet Brendan Bender

(Brendan Bender., 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 used 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. T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. Mechanism–based PK/pharmacodynamic (PKPD) models were developed that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. The variable patterns of platelet and transaminase (ALT and AST) response were quantified. Asian ethnicity was related to higher incidences of Grade 3/4 TCP and quantified via parameterization of covariate effect.  Model simulation strategies were developed to compare dose intensities and Grade 3/4 incidences between weekly T-DM1 regimens and the approved dose (3.6 mg/kg every three weeks), providing clinical guidance for T-DM1 development. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex PK of T-DM1, as a prototypical ADC, was elucidated through PK model development using in vitro and in vivo rat and cynomolgus monkey DAR data. 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. An integrated 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 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 understanding for ADC PK and PKPD (TCP and hepatotoxicity), and drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards efficient dose finding for anticancer drugs in development, especially ADCs., Härtill 4 uppsatser, Diss. (sammanfattning) Uppsala : Uppsala universitet, 2016)

Genre

Avhandlingar, theses

Språk

Engelska

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