Curriculum Vitae

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) focuses on methotrexate (MTX), a well-established drug widely used in different types of cancer. To reduce toxicity conveyed by high-dose MTX therapy, folinate is usually administered within 24 hours after MTX administration until the MTX plasma concentration drops below a predefined PK target using frequent blood sampling for this Therapeutic Drug Monitoring (TDM). The aim of this project is to optimise the TDM sampling schedule of MTX by developing a pharmacometric model to get further insights into sources of variability in the MTX clearance and subsequently use this knowledge to determine the most informative time point(s) for blood sampling to estimate a patient’s individual clearance (MIPD). By doing so, the number of blood samples needed from a patient shall be minimised and the rescue therapy with folinate in a clinical setting shall be improved.

Project 4 (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.