Model based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as... Show moreModel based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as variability of drug exposure and/or clinical response(s). This thesis __Pharmacogenomics in Drug Development: Implementation and Application of PKPD Model Based Approaches__ focused on genotype differences in explaining inter-individual variability in drug metabolism and clinical response. Population pharmacokinetic and pharmacodynamic models were developed to evaluate the relationship between exposure differences resulting from UGT2B15 genotype and their effects on both fasting plasma glucose and glycosylated haemoglobin for the type 2 diabetes drug, Sipoglitazar__. The model was used to quantify the optimal dose and regime (Single treatment/genotyped-based or titrated based upon response) for future clinical trials. Evaluating the potential impact of genetic differences early during development is important to appropriately design future clinical studies and to ensure that exposure response relationships for efficacy and safety can be identifed for all genetic subgroups. Ultimately, these model-based approaches can be used to determine if covariate-based dose individualization would be advantageous/beneficial to normalize exposure and minimize variability in clinical outcomes across heterogeneous clinical populations. Show less
Cardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach_... Show moreCardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach__, a system-specific model is described to quantify drug effects on the interrelationship between mean arterial pressure, cardiac output, heart rate, stroke volume and total peripheral resistance in rats. The developed model can be used to quantify and predict the dynamic changes in the cardiovascular system (CVS) and elucidate the mechanism of action of novel compounds. An ultimate application of this system-specific CVS model would be to facilitate the anticipation of the clinical response based on preclinical data for newly developed compounds. Furthermore, the developed system-specific CVS model was combined with receptor models to quantify and predict the cardiovascular effects of the sphingosine 1-phosphate (S1P) receptor agonists, fingolimod-phosphate (fingolimod-P)and siponimod, in rats. This systems pharmacology model provided a quantitative understanding of the cardiovascular effects of fingolimod-P and siponimod and can be applied to predict the cardiovascular effects of other S1P receptor agonists with different selectivity profiles in rats. Ultimately, it may constitute a basis for prediction of cardiovascular effects of S1P receptor agonists in humans Show less
Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by... Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold. Show less
Het onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking... Show moreHet onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking van dit concept voor een chronisch progressieve ziekte; postmenopausale osteoporose. De onderliggende aanname is dat een betere, samenhangende, beschrijving van dit soort ziektes wordt verkregen door de combinatie van 1) een wiskundige structuur gebaseerd op het onderliggende biologische mechanisme met 2) fysiologische data die de ziekteprogressie en de behandelingseffecten weergeven. Het onderzoek heeft aangetoond dat het modeleren van postmenopausale osteoporose op basis van een ziektesysteem analyse (__disease system analysis__) leidt tot waardevolle inzichten in zowel symptomatische als beschermende (ziekte modificerende) effecten op verschillende biologische markers. Er kan gesteld worden dat deze mechanistische ziektesystemen een __kennisbank__ kunnen en moeten vormen om een beter ge_nformeerd besluitvormingsproces tijdens de ontwikkeling (farmaceutische industrie), de beoordeling (overheden) en uiteindelijk het klinische gebruik van geneesmiddelen. Ziekteprogressie modellen maken het steeds beter mogelijk om informatie vanuit meerdere bronnen samen te voegen op basis van de kennis over het geneesmiddel en de ziekte. Met toenemende kennis over het systeem en de behandelingseffecten van bestaande en nieuwe geneesmiddelen kunnen deze modellen continue worden verbeterd en ingezet in het onderzoek en gebruik van deze middelen. Uiteindelijk leidt dit tot een meer effici_nte en kosteneffectieve benadering van geneesmiddelontwikkeling en het klinisch gebruik van geneesmiddelen. Het is van groot belang dat de farmaceutische industrie, academische instellingen en de overheid verder samenwerken aan het onderzoeken en vergroten van de mogelijkheden van een dergelijke gestructureerde aanpak (www.tipharma.nl). Show less
