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  • Periodic Reporting for period 1 - MEDLEM (Cost-effective microfluidic electronic devices for optimal drug administration based on fractional pharmacokinetics for leukemia treatments)

MEDLEM Report Summary

Project ID: 690876
Funded under: H2020-EU.1.3.3.

Periodic Reporting for period 1 - MEDLEM (Cost-effective microfluidic electronic devices for optimal drug administration based on fractional pharmacokinetics for leukemia treatments)

Reporting period: 2016-01-01 to 2017-12-31

Summary of the context and overall objectives of the project

The problem/issue being addressed: Leukemia is a group of cancers that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Worldwide, over 250000 people are diagnosed with leukaemia each year, accounting for 2.5% of all cancers. An estimated 75000 new patients of leukemia can be diagnosed in Europe each year. All age groups can be affected; leukemias are the most common pediatric tumor (35% of cancers in children aged 0-14 years). The breakthroughs in diagnostics, therapy and improvements to therapy protocols have all led to long-term curing, with an overall five-year survival rate of almost 80% in children with Acute Lymphoblastic Leukaemia (ALL). There is an utmost need for new treatments and new high-tech devices which can help in customized therapy of leukemias. The MEDLEM project addresses this challenge. Namely, implementation of this Project will help in both detection of high risk patients, especially children, and general improvement of the human condition during invasive treatment what chemotherapy definitely is.

Why is it important for society? The solution, which promises to transform treatments for many diseases that require frequent and carefully regulated doses of medication, is being developed in the MEDLEM initiative, a unique collaborative project bringing together researchers and companies from France, Germany, Serbia, Australia and Thailand. The MEDLEM project is coordinated by the University of Novi Sad, Serbia and members of the consortium include three companies from EU (Elvesys and Genochem from France and Marcotech from Germany) as well as two universities outside of EU – Prince Songkla University from Thailand and Curtin University from Australia. The main idea of this Project is an optimal control problem: which chemotherapy is to be assigned to each individual patient in order to improve the chances for cure, decrease side effects and ensure that the total toxicity is below an allowable limit. The MEDLEM consortium capitalises on the diverse, yet well-rounded experience in order to exchange knowledge and transform currently outdated treatment for leukaemia patients. Building on the experience of each team member, the MEDLEM project aims at bringing new technologies together, to form a comprehensive, integrative, multi-functional and patient-tailored therapy, using cutting-edge techniques and real-time analysis of patients’ well-being and response to medications. This will enable accurate, precise and concise medical measurements will improve therapy and reduce side effects, and thus, transform patients’ experience and long-term prognosis. The widespread use of micro-fluidic chips enabling personalised dosing will improve long-term prognoses, especially in children.

What are the overall objectives? The goal of the MEDLEM project is to enhance therapy and reduce treatment side effects, improving patients’ quality of life and their long-term prognosis. Its overall objective is to increase five and ten-year survival rates of patients with leukaemia, in Europe and globally.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The main scientific results achieved so far:
• Re-examined recently developed fractional pharmacokinetic models and integer order pharmacokinetic models dealing with methotrexate (MTX);
• Proposed a new model that will take into account both specific MTX deposition/restoring processes and monitoring of the kidney compartment;
• Examined existing MTX administration protocols and proposed a new one, which will be realized by the microfluidic electronic device and used in system parameter identification for individualized treatment;
• 2 microfluidic electronic devices (chips) have been developed in PCB (printed circuit board technology);
• 4 microfluidic electronic devices (chips) have been developed in multilayer flexible PVC technology;
• 2 microfluidic micromixers have been developed in sophisticated PDMS (PolyDiMethylSiloxane) technology;
• Structural, mechanical and electrical characterization and testing of manufactured microfluidic chips has been performed;

• Established an analytical method for MTX and its metabolites analyses in biological fluids;
• Optimal pharmacokinetic model and its parameters after low and high doses regimes of MTX in different compartments has been determined.

The other important results achieved so far:
• 22 secondments were performed (7 intersectoral and 15 international);
• 39 performed secondments months (13 intersectoral and 26 international; 33 funded from the project budget and 6 funded from additional sources);
• 1 Workshop and 1 Summer School organized;
• 11 published papers in scientific journals;
• 2 book chapter published;
• 17 conference papers reported;
• 95 dissemination and communication event attended;
• 175 students trained in microfluidic / entrepreneurship / fractional calculus;
• 6 Project Management Board meetings organized;
• 5 follow-up project proposals submitted.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The MEDLEM work has been focused on two main tasks: firstly, capturing pathology and physiology data in computer models combined with specific data about the health and treatment responses of individual patients in order to test the dynamics of different drug administration procedures. Secondly, we will use this data to define an optimal dosing solution implemented via a smart micro-fluidic device.

The approach constitutes a state-of-the-art implementation of fractional pharmacokinetics, an emerging field of pharmacokinetics that uses mathematical modelling to study quantitatively the course and accumulation of specific drugs in the body. Applied in a clinical setting, this will enable doctors to define which chemotherapy strategy should be assigned to each individual patient based on their physiology and pathology, ensuring effective treatment, decreased side effects and maintaining drug toxicity below permitted limits. It will solve the current problem of uncontrolled dosing regimens in which the amount and frequency of each dose is defined by broad guidelines but not tailored to meet each individual patient’s needs, providing instead optimised, personalised chemotherapy.
The project team plan to test their approach in both laboratory and clinical trials to control doses of methotrexate, a commonly used anti-metabolite in cancer therapy that has a wide dosage range and an antidote in clinical use.

The H2020 MEDLEM project provides modern, flexible microfluidic chips capable of delivering drugs on optimal way using personalized and tailored nano and micro technologies. Furthermore, microfluidic chips are already fabricated using xerographic technology or PDMS (PolyDiMethylSiloxane) technology, and they are low cost, light weight and shock resistant. Additional advantages of the proposed technology for biomedical research rely on capability to apply complex protocols on flow control, using microcontroller based microfluidic device, which will rely on the theoretically predicted optimal flow.

Among the variety of all possible choices that can be used, the MEDLEM addresses pharmacokinetic of methotrexate (MTX). Being the most commonly used antimetabolite in cancer therapy, MTX was chosen for its widest dose range and a property of having an antidote in clinical use (leucovorine). A special feature of this study will be monitoring and recognition of potential problems in the beginning of MTX administration.

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