Pharmacokinetic insights in individual drug response: A model-based approach to quantify individual exposure-response relationships in type 2 diabetes

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Patients with diabetic kidney disease have an increased risk of developing cardiovascular and kidney complications, which contributes to a substantial reduction in quality of life and life expectancy. The current standard of care comprises treatment with renin-angiotensin-aldosterone system inhibitors, which reduce albuminuria and delay the progressive loss of kidney function. More recently, sodium-glucose co-linked transporter-2 inhibitors have been a welcome addition to the therapeutic armamentarium that demonstrated similar kidney protective effects. Despite the fact that renin-angiotensin-aldosterone system inhibitors and sodium-glucose co-linked transporter-2 inhibitors have improved the prognosis of patients, the residual risk of developing cardiovascular and kidney complications remains high, which emphasises the continued unmet need to develop new treatment strategies that target the progressive kidney function loss. Drug development in this area has however not been very successful, which can, at least in part, be attributed to inadequate dose selection and high between-subject variability. Moreover, drug developers and regulators pay insufficient attention to off-target drug effects when selecting the dose for confirmatory studies. High between-subject variability also affects clinical practice. Clinicians translate results of large outcome trials to an individual patient, but both treatment guidelines and clinical trials are not designed to take variability between-patients into account. Therefore, individual treatment of patients is often suboptimal . This thesis aims to improve the understanding of variability in anti-diabetic drug response by quantifying the dose-exposure-response relationship. Quantifying the dose-exposure-response relationship provides the opportunity to identify predictors for treatment response and additionally provides insight whether dose modifications could improve individual treatment response.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Lambers Heerspink, Hiddo, Supervisor
    • Mol, Peter, Supervisor
    • Stevens, Jasper, Co-supervisor
    • de Boer, A., Assessment committee, External person
    • van Gelder, T., Assessment committee, External person
    • Struys, Michel, Assessment committee
    Award date18-Jan-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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