Anna Mc Laughlin (nee Müller-Schöll)
PharMetrX Research+ Program
PhD student year: 2018
University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: SANOFI
Model-informed precision dosing for targeted anticancer drugs (working title)
The focus of my research is to optimise modern anticancer drug treatment for the individual patient by combining therapeutic drug monitoring with a pharmacometric modelling & simulation approach.
Over the past 20 years, anticancer drug treatment has changed substantially from mostly untargeted, cytotoxic intravenous chemotherapy to novel therapeutic options like monoclonal antibodies, targeted oral anticancer drugs (tOADs) and immunotherapy. Although this change in treatment paradigm has improved the prognosis of many cancers dramatically, there are still some challenges to address:
Project 1: Targeted oral anticancer drugs (tOADs)
The field of tOADs is rapidly advancing and includes targeted antihormonal drugs, protein kinase inhibitors (KIs) and others. With 38 compounds approved since 2001, tyrosine kinase inhibitors (TKIs) form the biggest and fastest evolving subclass, targeting specific mutations, involved in a variety of cancers. tOADs typically show complex pharmacokinetics, a narrow therapeutic window and a high potential for (serious) adverse events. Nevertheless, at the currently practised “one-dose-fits-all” approach, every patient receives the same dosing regimen, ignoring the aforementioned complexities and resulting in up to 16-fold different exposures in individual patients. While subtherapeutic drug concentrations can lead to loss of efficacy, supratherapeutic drug concentrations can result in severe adverse reactions and ultimately in low adherence or even treatment discontinuation. In my work, I research on opportunities to individualise dosing regimens for tOADs based on patient-specific characteristics, drug properties and established or promising therapeutic targets, using model-informed precision dosing (MIPD). MIPD is based on the of use pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation to estimate population and patient-individual PK/PD parameters, to assess the probability of therapeutic target attainment under different dosing regimens and to make rational choices for the (initial) dosing of patients. Ultimately, this allows choosing the right dose for the individual patient, thereby maximising treatment efficacy and minimising toxicity.
Currently, I focus on the antihormonal drug tamoxifen and on tyrosine kinase inhibitors.
Project 2: Chimeric antigen receptor T cells (CAR-T cells)
CAR-T cells are an exciting new treatment option in the field of cancer immunotherapy. In short, T cells are extracted from a patient’s blood and genetically engineered to express a synthetic chimeric antigen receptor (CAR), targeting the patient’s tumour cells. After a 1-2 week expansion period, the manufactured T cells are infused back into the patient, where they specifically detect and kill cancer cells. While there has been remarkable success in the treatment of several forms of blood cancer, open challenges remain: While CAR-T cells rapidly expand and persist for years in some patients, they do not survive in others, resulting in loss of efficacy and cancer progression. Several factors might influence the expansion and, most importantly, long-term persistence of CAR-T cells. These include the frequencies of distinct CAR-T cell phenotypes in the infusion product, type and intensity of lymphodepleting chemotherapy, tumour burden and levels of several cytokines. In this project, by applying a systems-driven semi-mechanistic modelling & simulation framework, I aim to investigate the relevance of aforementioned factors for CAR-T cell expansion and persistence, in order to explore rational strategies towards increased treatment success.
Please see the list of all publications and PhD theses.
- Since 07/2018: PhD student of the Graduate Research Training Program “PharMetrX: Pharmacometrics & Computational Disease Modelling“ supervised by Prof. Dr. Charlotte Kloft at the Dept. of Clinical Pharmacy & Biochemistry, Freie Universität Berlin
- 07/2018: Registered Pharmacist
- 11/2017-04/2018: Pre-registration pharmacist at 'Apotheke im Helmholtzplatz', Berlin
- 05/2017-10/2017: Pre-registration pharmacist at Pfizer Pharma GmbH, Berlin
- 09/2015-04/2017: Student research fellow in the Analytics & Metabolism group of Prof. Dr. Parr in the Department of Pharmaceutical Chemistry, Freie Universität Berlin
- 02/2014: Internship at 'Spitzweg Apotheke', Stuttgart
- 08/2013: Internship in the hospital pharmacy of the Robert-Bosch-Hospital, Stuttgart
- 04/2013-04/2017: Studies of Pharmacy at the Freie Universität Berlin