Students
Fenja Klima
Pharmacist / University of Freiburg
PharMetrX Research+ Program
PhD student year: 2022
University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: AstraZeneca
PhD Project
Model-informed precision dosing for novel and established therapeutic modalities in oncology
Cancer is one of the leading death causes worldwide. An effective and safe anticancer therapy is therefore of high importance: While subtherapeutic plasma concentrations may be life-threatening due to therapy failure, a too high exposure with anticancer drugs elevates the risk for potentially severe adverse drug reactions (ADR)/toxicity. During the past 30 years, new therapeutic modalities such as small molecule kinase inhibitors and immunotherapies have been developed, allowing a more specific targeting of tumour cells. At the same time, well-established antihormonal or cytotoxic anticancer drugs remain an important pillar of cancer therapy. Many of these drugs display highly variable pharmacokinetics (PK)/ pharmacodynamics (PD) between individuals. Nevertheless, in most cases dosing regimens still follow a ‘one-dose-fits-all’ principle, thereby reducing the efficacy of anticancer treatment or increasing the risk for drug toxicity. Pharmacometric modelling and simulation enables to characterise patient-drug-disease relationships and to identify sources of interindividual variability. Its application in model-informed precision dosing (MIPD) allows to account for individual characteristics of patients and their disease and to leverage the full potential of a selected anticancer treatment.
In this context, my doctoral thesis aims at facilitating and establishing MIPD in the field of oncology. In several projects, I will focus on different steps on the path to implementing MIPD from clinical development to clinical practice. Each project focuses on a different established or novel (targeted) drug or therapeutic modality used in anticancer therapy.
Project 1 (early-stage clinical development) focuses on chimeric antigen receptor (CAR)-T cell therapy, which is an exciting novel approach in the field of cellular immunotherapy but reasons why some patients respond well and others don’t are yet unclear. In a nutshell, T cells are extracted from a patient’s blood, genetically modified in order to target the patient’s tumour cells and re-infused back into the patient to specifically kill cancer cells. The project aims to explore and improve early response prediction for CAR-T cell therapy by validating and expanding our previously developed quantitative systems pharmacology model in order to ultimately identify individual treatment success with CAR-T cells.
In Project 2 (late-stage clinical development), I will work on tamoxifen, which is well-established in the treatment of oestrogen receptor-positive breast cancer. The formation of its active metabolite endoxifen is highly dependent on the metabolic enzyme CYP2D6, which displays variable activity in particular due to polymorphism. This project aims to investigate the proposed and heavily discussed exposure-response relationship for endoxifen leveraging the largest available database on tamoxifen therapy in breast cancer patients using pharmacometric modelling and simulation approaches and thereby to enable individualised dosing for tamoxifen.
Project 3 (MIPD in clinical practice) aims at establishing a nationwide infrastructure for a pharmacometric-based closed-loop TDM service for targeted oral anticancer drugs (tOAD) in clinical practice. tOAD like tyrosine kinase inhibitors often display a small therapeutic window and high interindividual pharmacokinetic variability, thereby potentially benefitting from individualised dosing. Within the framework of the already initiated ON-TARGET pilot study (www.fu-berlin.de/on-target), primary study goals are to assess the feasibility and degree of implementation of the conducted closed-loop TDM process in clinical practice and the potential of routine use of TDM for reduction of ADR. Furthermore, the feasibility of capillary instead of venous blood sampling for TDM will be investigated.
Publications
Please see the list of all publications and PhD theses.
Education
- 03/2022: Entering PharMetrX
- 12/2021: Registration as a Pharmacist
- 05/2021-10/2021: Pharmacist in pre-registration year at F. Hoffmann-La Roche AG, department for drug delivery & preformulation sciences
- 11/2020-04/2021: Pharmacist in pre-registration year, Haslach Apotheke, Freiburg i.Br.
- 09-10/2019: Internship at the Institute of Pharmaceutical Sciences at the University of Freiburg, AK Prof. Jung
- 09/2015: Internship at hospital pharmacy of the Rems-Murr-Klinikum, Winnenden
- 03/2015: Internship at Holzmarktapotheke, Freiburg i.Br.
- 10/2016-10/2020: Studies of Pharmacy, University of Freiburg
- 06/2015: Abitur, Albertus-Magnus-Gymnasium Stuttgart