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Yersultan Mirasbekov
MSc Innovative Medicine / Uppsala University

PharMetrX Research+ Program
PhD student year: 2024

University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: Roche

PhD Project

Optimising Therapeutic Strategies through Pharmacometrics

Therapy progression for specific diseases is typically analysed through sample populations and the relationship between system, disease, and drug. Very often, clinical trials of novel therapies and treatment approaches are initially conducted in healthy adults to understand how the drug concentration-time profile behaves with the healthy system before proceeding to clinical trials involving the patient population. Yet, the translation and applicability of results from healthy individuals to special populations are often complicated due to changes in physiology and, consequently, pharmacokinetic processes. To ensure the safety and efficacy of the treatment of patients, the effects of these changes should be thoroughly examined and evaluated. This doctoral project is focused on the evaluation and optimisation, when needed, of anti-infective therapy for patients with obesity or pleural empyema, and hormonal replacement therapy for paediatric patients with congenital adrenal hyperplasia (CAH).

Project 1 of my doctoral studies will be focused on the characterisation of the pharmacokinetic and pharmacodynamic relationship between the patient, infectious pathogen, and antibiotic, which is essential for providing safe and effective antibiotic treatment. In patients with obesity, pharmacokinetic characteristics are often altered due to changes e.g., in body composition and physiology, requiring individualised exposure profiles of anti-infective drugs. Also, incorrect usage of body size descriptors in anti-infective dosing and regimens might have a negative impact on treatment success by causing bacterial resistance or drug toxicity [1, 2]. According to WHO, 890 million adults were living with obesity in 2022, which is approximately 1 in 8 people in the world [3]. Therefore, there is a need for further investigation of the difference between non-obese and morbidly obese patients to optimise dosing regimens. To ensure the evaluation of antibiotics at the target site, the microdialysis technique is applied to measure interstitial space fluid exposure in tissues/organs of interest [4]. Measurements in the interstitial space fluid of the adipose tissue will be used in the development of population pharmacokinetic and pharmacodynamic models using nonlinear mixed-effects (NLME) modelling to assess the suitability of anti-infective dosing regimens [5]. Pharmacokinetic and pharmacodynamic models will be developed using plasma and target-site concentrations for various antibiotics, namely tigecycline, and metronidazole, from available clinical studies, enabling the evaluation and, if needed, optimisation of antibiotic therapy. Additionally, the research findings and developed methods will be transferred to study and assess antibiotic therapy in patients with pleural empyema who undergo cardiopulmonary bypass. The lung microdialysis will be performed to measure antibiotic concentration in pleural space in patients with pleural empyema and to compare it to measured concentrations in plasma, intercostal muscles, subcutaneous tissue, and lung tissue.

Project 2 of my doctoral studies will be focused on cortisol replacement therapy for paediatric patients with CAH. CAH is a group of inherited genetic disorders leading to impaired steroidogenesis [6]. The most common form (> 90% of cases), also known as the classic form, is caused by a deficiency/absence of the 21-hydroxylase enzyme activity, which is involved in the biosynthesis pathway of glucocorticoids, such as cortisol, and mineralocorticoids [6, 7, 8]. Additionally, the substantial decrease in cortisol concentration reduces feedback mechanisms, which causes increased production of corticotropin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) in the hypothalamus and pituitary gland, respectively. The increase in ACTH, navigated by the hypothalamic-pituitary axis, is the main reason for the overproduction of androgens and androgen precursors [7, 9]. The doctoral study prioritises addressing the reduced or absent cortisol production through hydrocortisone replacement therapy, with particular attention to mimicking cortisol's circadian rhythm. However, in the context of current CAH treatment, the hydrocortisone replacement therapy fails to mimic the physiological cortisol circadian rhythm [10]. Optimisation and individualisation of the therapy might maintain homeostasis, and bring the patient's cortisol levels closer to the cortisol circadian rhythm in the healthy state. Previously developed pharmacokinetic models will be adapted and expanded to explain the change in cortisol and ACTH concentrations during hydrocortisone replacement therapy from currently available and upcoming clinical studies [11, 12, 13, 14]. The improved understanding of hydrocortisone pharmacokinetics and the endogenous cortisol-producing system will be leveraged for therapy evaluation and optimisation, aiming toward therapy individualisation.

For both projects, pharmacometric approaches will be applied for the modelling and simulation of concentration-time and exposure-response profiles, especially due to the limited amount of data from clinical studies. The use of NLME modelling will enable an analysis of population-specific concentration-time profiles using typical population values and random effects to characterise the variability among individuals [15, 16]. Also, available individual demographics and characteristics will be used as a covariate to explain possible variability from typical population values [17]. The resulting models will serve as the foundation for the evaluation and optimisation of therapies adapted to special populations.

References list:

  1. Busse, D., Simon, P., Petroff, D., El-Najjar, N., Schmitt, L., Bindellini, D., Dietrich, A., Zeitlinger, M., Huisinga, W., Michelet, R. and Wrigge, H., 2022. High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients. Antimicrobial Agents and Chemotherapy, 66(6), pp.e02302-21.
  2. Pai, M.P., 2021. Antimicrobial dosing in specific populations and novel clinical methodologies: obesity. Clinical Pharmacology & Therapeutics, 109(4), pp.942-951.
  3. World Health Organization, 2023. Obesity and overweight. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Last accessed in June 10, 2024.
  4. Plock, N. and Kloft, C., 2005. Microdialysis—theoretical background and recent implementation in applied life-sciences. European journal of pharmaceutical sciences, 25(1), pp.1-24.
  5. European Medicines Agency. 2017. Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products. European Medicines Agency. https://www.ema.europa.eu/en/use-pharmacokinetics-pharmacodynamics-development-antibacterial-medicinal-products. Last accessed in 10 June 2024.
  6. Speiser, P.W., Arlt, W., Auchus, R.J., Baskin, L.S., Conway, G.S., Merke, D.P., Meyer-Bahlburg, H.F., Miller, W.L., Murad, M.H., Oberfield, S.E. and White, P.C., 2018. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 103(11), pp.4043-4088.
  7. Merke, D.P. and Auchus, R.J., 2020. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. New England Journal of Medicine, 383(13), pp.1248-1261.
  8. White, P.C. and Speiser, P.W., 2000. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine reviews, 21(3), pp.245-291.
  9. Claahsen-van der Grinten, H.L., Speiser, P.W., Ahmed, S.F., Arlt, W., Auchus, R.J., Falhammar, H., Flück, C.E., Guasti, L., Huebner, A., Kortmann, B.B. and Krone, N., 2022. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocrine reviews, 43(1), pp.91-159.
  10. Mah, P.M., Jenkins, R.C., Rostami‐Hodjegan, A., Newell‐Price, J., Doane, A., Ibbotson, V., Tucker, G.T. and Ross, R.J., 2004. Weight‐related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clinical endocrinology, 61(3), pp.367-375.
  11. Melin, J., Parra-Guillen, Z.P., Michelet, R., Truong, T., Huisinga, W., Hartung, N., Hindmarsh, P. and Kloft, C., 2020. Pharmacokinetic/pharmacodynamic evaluation of hydrocortisone therapy in pediatric patients with congenital adrenal hyperplasia. The Journal of Clinical Endocrinology & Metabolism, 105(4), pp.e1729-e1740.
  12. Michelet, R., Bindellini, D., Melin, J., Neumann, U., Blankenstein, O., Huisinga, W., Johnson, T.N., Whitaker, M.J., Ross, R. and Kloft, C., 2023. Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach. Frontiers in Pharmacology, 13, p.1090554.
  13. Michelet, R., Melin, J., Parra-Guillen, Z.P., Neumann, U., Whitaker, J.M., Stachanow, V., Huisinga, W., Porter, J., Blankenstein, O., Ross, R.J. and Kloft, C., 2020. Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children. European Journal of Endocrinology, 183(4), pp.357-368.
  14. Fisher, D. (2007). Fisher/Shafer NONMEM Workshop Pharmacokinetic and Pharmacodynamic Analysis with NONMEM. Basic Concepts.
  15. Bindellini, D., Michelet, R., Aulin, L., Melin, J., Neumann, U., Blankenstein, O., Huisinga, W., Whitaker, M.J., Ross, R. and Kloft, C., 2024. A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy. Journal of Pharmacokinetics and Pharmacodynamics, pp.1-16.
  16. Mould, D.R. and Upton, R.N., 2012. Basic concepts in population modeling, simulation, and model‐based drug development. CPT: pharmacometrics & systems pharmacology, 1(9), pp.1-14.
  17. Mould, D.R. and Upton, R.N., 2013. Basic concepts in population modeling, simulation, and model‐based drug development—part 2: introduction to pharmacokinetic modeling methods. CPT: pharmacometrics & systems pharmacology, 2(4), pp.1-14.

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Publications

Please see the list of all publications and PhD theses.

Education

  • 03/2024: Entering PharMetrX
  • 09/2022 – 07/2023: Med.Sc. in Medical Science, Uppsala University, Sweden
    - Internship at Department of Pharmacy, Uppsala University, Sweden
    - Master’s thesis work at Department of Pharmacy, Uppsala University, Sweden
  • 09/2021 – 08/2022: Sc. in Translational Medical Research, Heidelberg University, Germany
    (Part of International Master's Programme in Innovative Medicine)
    - Internship at Joint Research Center for Computational Medicine, University Hospital RWTH Aachen, Germany
  • 08/2016 – 06/2020: Sc. in Biological Sciences at Nazarbayev University, Kazakhstan
    - Research as a member of iGEM team at Nazarbayev University, Kazakhstan
    - Internship at Division of Biomolecular Function Discovery, Bioinformatics Institute, Singapore
    - Exchange semester at University of Tsukuba, Japan
    - Internship at Department of Pharmacy, Ludwig Maximilian University of Munich, Germany
    - Bachelor’s thesis work at Biophotonics and Living Systems Laboratory, Nazarbayev University, Kazakhstan