Students
Zrinka Duvnjak
Master of Pharmacy (MPharm) / University of Zagreb, Croatia
PharMetrX Research+ Program
PhD student year: 2023
University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: Roche
PhD Project
Understanding the immunogenicity of monoclonal antibodies in patients with different inflammatory diseases
Therapeutic proteins, particularly monoclonal antibodies (mAbs), have emerged as a crucial class of drugs over the past two decades, with an increasing presence in therapeutic use. They are produced by living organisms, so human immune system reacts to them after administration by producing (ADAs), which in turn can neutralise drug effect or increase its clearance. The development of ADAs poses a significant challenge in the treatment of various diseases. It is a multifaceted process influenced by factors such as drug-, disease-, and individual patient-related characteristics. My doctoral project aims to delve into the intricacies of immunogenicity and its impact on treatment outcomes, focussing on the widely used monoclonal antibody, infliximab, in the context of inflammatory diseases.
Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis are inflammatory diseases that pose significant medical challenges worldwide. Characteristics of these diseases is persistent inflammation and tissue damage in which Infliximab plays a critical role in managing these conditions by targeting TNF-alpha, one of the important mediators of inflammation and this way suppressing the immune response. Even though effective, 50% of patients fail to respond to treatment within the first year and ADAs are one of the reasons for it.
As mAb are nowadays a very important drug class in therapeutic use, it is crucial to understand their pharmacokinetic (PK) and pharmacodynamic (PD) properties and what affects them to be able to give a right drug, to the right patient, following the optimal dosing regime.
Pharmacometrics, a discipline combining pharmaceutical sciences, pathophysiology, medicine, mathematics, and statistics, plays a vital role in optimising treatment outcomes. While population, or so-called nonlinear mixed-effects pharmacokinetic models (NLME), are already rather established for PK/PD modelling, modelling of immunogenicity presents several challenges, primarily due to the biological complexity in the formation of ADAs and the limitations of bioanalytical methods used to quantify ADAs.
In part I, this project aims to develop NLME (population) PK/PD models to understand the drug exposure–response relationship for different inflammatory diseases (Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis), taking into account their different pathophysiological characteristics, with the highlight on common biomarkers. As part II of this project, immunogenicity models will be developed for populations of patients with inflammatory diseases, as well as for healthy volunteers, to comprehend its relationship with the diseases and infliximab. In the final part III of the doctoral project, by integrating these two aspects – exposure-response relationships and immunogenicity (joint immunogenicity-exposure-response model) –, the project finally aims to shed light on the interplay between immune response, mAb and pathophysiology of different inflammatory diseases in patients with different individual characteristics and its effect on exposure and treatment efficacy. In addition to classical pharmacometric modelling approaches, this doctoral project will employ other model approaches, such as mixed hidden Markov models, to overcome the challenges associated with immunogenicity assessments. By incorporating these advanced modelling approaches, the project aims to enhance the accuracy and reliability of pharmacometrics models currently used. The data used in the project originates from different phase III clinical trials from our clinical collaboration partners; and drug, immune system, diseases and patient characteristics will be taken into account. The ultimate objective of this doctoral project is to advance the understanding of the complex interplay between inflammatory diseases, infliximab, immune response, and patient characteristics by a joint immunogenicity exposure-response model. This will allow for precision dosing and optimisation of infliximab treatment outcomes in the context of inflammatory diseases. Moreover, this project will broaden the knowledge about ADA formation and allow the potential application of developed models on other therapeutic proteins and diseases.
Publications
Please see the list of all publications and PhD theses.
Education
- 06/2023: Entering PharMetrX
- 10/2022-04/2023: Internship at F. Hoffmann-La Roche Ltd, predictive modeling and data analytics chapter
– Simulation-based evaluation of the Pharmpy Automatic Model Development (AMD) tool for population pharmacokinetic model building - 05/2022-09/2022: Internship at Freie Universität Berlin, Department of Clinical Pharmacy and Biochemistry
– Performance comparison of Phoenix WinNonlin NCA and qpNCA
– Tigecycline atypical plasma protein binding model - 10/2021-04/2022: Pre-registration pharmacist
- 03/2021-07/2021: Internship at University of Helsinki, Division of Pharmaceutical Chemistry and Technology
– Microfluidic immobilized enzyme microreactor for intestinal drug metabolism research (master’s thesis) - 11/2020-02/2021: Internship at Xellia Pharmaceuticals
– Preparation and characterisation of therapeutic glycopeptide-loaded liposomes - 06/2019-09/2019: Internship at University of Cambridge, Department of Pharmacology
– Identifying naturally-occurring chemical scaffolds as novel PARP inhibitors by integrating in silico and in vitro methods - 09/2017-09/2018: Internship at University of Zagreb, Department of General and Inorganic Chemistry
– Kinetics and mechanism of activation of C – H bond in azobenzenes by Pd(II) catalyst - 10/2016-04/2022: MPharm degree at University of Zagreb, Faculty of Pharmacy and Biochemistry