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Applying pharmacometric modelling andsimulations in non-alcoholic fatty liver diseaseto better understand translatability ofpreclinical animal models and fibrosisprogression in patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2019 (English)Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
Abstract [en]

AbstractThe economic and health burden of non-alcoholic fatty liver disease (NAFLD) is increasing. To this day, there does not exist an approved drug therapy for NAFLD. NAFLD drug development is facing many challenges. One challenge is to find the right preclinical animal model that could mimic both physiological and histopathological properties of NAFLD. Those animal models can be used to study the mechanism of disease progression and to investigate novel treatments before the first time in human study is initiated. Furthermore, there is a great need to better understand NAFLD with a high focus to understand fibrosis progression, as it is the best predictor of disease morbidity and mortality. There is also a need to differentiate high and low risk NAFLD populations for tailored individual treatment and improved inclusion criteria for clinical trials. The aims of this thesis were to apply pharmacometric modelling and simulations to investigate the clinical translatability of the preclinical DIO-NASH and ob/ob-NASH models and to understand the fibrosis progression with the factors contributing to it in NAFLD patients. The quantitative translatability of both mouse models (DIO-NASH and ob/ob-NASH) was assessed from preclinic to clinic setting by investigating the pharmacodynamic actions of liraglutide, obeticholic acid and elafibranor with respect to their exposures and potencies. Those exposures were obtained by simulating the dose regimens given in the corresponding preclinical/clinical study using pharmacokinetic modelling and simulations. Both mouse models demonstrate a consistent behavior regarding the exposure that produces the required effect as well as pharmacodynamic action of OCA. Some variations on translation were demonstrated with the other two compounds. In general, this work supports the use of diet-induced NASH models to evaluate treatment effects. Further, a continuous-time Markov model with first order markovian features was used to describe the forward and backward transition rates between different fibrosis stages in a longitudinal data of long-term follow-up biopsy in NAFLD patients. The developed model well described the transition rates to death state either due to cardiovascular/liver related or any other cause of mortality as well as the transition rate to drop-out state. Also, selected covariate effects were assessed, where age exponentially increased risk of fibrosis progression as well as dying, and both body mass index in non-obese and NAFLD activity score exponentially increased risk of progression from fibrosis stage 0 to 3, while body mass index effect was constant in obese. Also, the transition rates to death increased exponentially with the increase in the fibrosis stages from stage 3 and above. To our knowledge, this is the first markovian model of fibrosis progression in NAFLD, and is a good start to continue investigating biomarkers for fibrosis progression, include drug effects as predictors and perform clinical trial simulations.

Place, publisher, year, edition, pages
2019. , p. 54
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-390894OAI: oai:DiVA.org:uu-390894DiVA, id: diva2:1343095
External cooperation
AstraZeneca, Gothenburg
Supervisors
Examiners
Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-08-15Bibliographically approved

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