Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium... Show moreZebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. Paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf. Show less
The aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A... Show moreThe aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A physiologically-based pharmacokinetic simulation workflow was developed to unravel the conditions for accurate scaling of drug clearance from adults to children as young as term neonates of one day for various methods. This disproved the belief that a universal allometric exponent can scale size-related changes in clearance across the paediatric age range, and showed that isoenzyme maturation and drug properties, especially extraction ratio and drug binding to alpha-1-acid glycoprotein, should be accounted for when scaling clearance to young children. Based on these results, a clearance scaling decision tree is proposed, which allows pharmacologists for the first-time to select scaling method(s) that require a minimum but still sufficient amount of information to accurately scale clearance of drugs with known properties to a desired paediatric age-range. Moreover, an analysis framework is provided to assess the feasibility and clinical trial requirements for the estimation of PBPK parameters using population pharmacokinetic modelling, which has the potential to expedite development of PBPK models for understudied paediatric subpopulations. Show less
In this thesis we describe the latest developments in the field of advanced thyroid cancer. Several clinical trials with sorafenib and everolimus were performed. The relation between clinical... Show moreIn this thesis we describe the latest developments in the field of advanced thyroid cancer. Several clinical trials with sorafenib and everolimus were performed. The relation between clinical outcome and mutational status was analyzed. Furthermore, the pharmacokinetics of everolimus in patients with advanced thyroid cancer was described. Show less
Biopharmaceuticals are among the most celebrated drugs. However, despite decades of experience, our understanding of many in vivo pharmacokinetic and adverse effects of biopharmaceuticals is... Show moreBiopharmaceuticals are among the most celebrated drugs. However, despite decades of experience, our understanding of many in vivo pharmacokinetic and adverse effects of biopharmaceuticals is still limited. These include the delay in reaching the maximum plasma concentration for an intravenously administered therapeutical protein, and the highly variable plasma concentration during elimination of monoclonal antibodies. Both observations can be explained by dynamical binding (‘stickiness’) of proteins to various (bodily) surfaces. Biopharmaceuticals also frequently contain (non-human) impurities, some of which are harmful when administered (‘dirtiness’). This toxicity often is the result of an intricate interplay of multiple cell types and effector pathways which can be difficult to simulate in the laboratory. More sophisticated test platforms are available, which can detect a number of untoward reactions that would previously not have been discovered. However, no laboratory test is fail-safe, and awareness of the possibility of adverse immunostimulation caused by biopharmaceuticals is the most important aspect for early detection and prevention of such cases in the future. Show less
Krens, L.L.; Baas, J.M.; Guchelaar, H.J.; Gelderblom, H. 2018
Sunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying... Show moreSunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying how genetic variations could influence drug response. The objective of this thesis was to find genetic markers that can predict toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma. This research builds upon previous findings from candidate gene studies by testing a selection of SNPs based on plausible involvement in pharmacokinetics or pharmacodynamics of the drug of interest. We observed that SNPs located in genes involved in metabolism and drug absorption (CYP3A4, CYP3A5, and ABCB1) are potentially associated with the clearance of sunitinib and its active metabolite. In analogy to this, we confirmed SNP associations from previous studies for SNPs in CYP3A5 and ABCB1 that predict the need for dose reductions and improvement of PFS on sunitinib. Sunitinib-induced toxicity is possibly related to SNPs in CYP3A4 and CYP3A5, and in interleukin genes IL8 and IL13. VEGFR-2 (KDR) rs34231037 G-allele variant carriers were potentially associated with a favorable response to sunitinib. A GWAS learned us that SNPs in chromosome 21 are involved in sunitinib efficacy, probably by influencing drug resistance mechanisms. Show less
Rein, N. van; Biedermann, J.S.; Bonafacio, S.M.; Kruip, M.J.H.A.; Meer, F.J.M. van der; Lijfering, W.M. 2016
Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these... Show more Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these populations, pharmacokinetic studies are needed to provide a basis for evidence-based dosing guidelines. In this thesis, we studied the pharmacokinetics of the CYP3A substrate midazolam, the renally excreted drug metformin and acetaminophen (metabolized by glucuronidation, sulphation and CYP2E1) in obese adolescents and/or morbidly obese adults. We address several currently unanswered questions; Can doses for obese adolescents be predicted on the basis of data obtained in morbidly obese adults? How to analyse pharmacokinetic data in obese adolescents, for whom body weight is influenced by growth, age and obesity? How to achieve safe and effective acetaminophen dosing for morbidly obese patients? The studies described in this thesis contribute to the existing gaps in knowledge regarding the pharmacokinetics and evidence-based dosing of drugs in obese adolescents and morbidly obese adults. Show less
Both tyrosine kinase inhibitors (tki) and mammalian target of rapamycin (mTOR) inhibitors are oral targeted therapies that are used for the treatment of a variety of malignancies. Due to the... Show moreBoth tyrosine kinase inhibitors (tki) and mammalian target of rapamycin (mTOR) inhibitors are oral targeted therapies that are used for the treatment of a variety of malignancies. Due to the growing evidence for drug exposure-response relationships, in combination with their high interpatient variability in pharmacokinetics (pk) and a fixed dosing regimen, it is hypothesized that dose individualization of oral targeted therapies may lead to better treatment outcomes both in terms of efficacy as well as toxicity. This thesis describes the results of different studies that investigated dose optimization strategies of oral targeted therapies used in oncology, with a focus on the TKIs pazopanib and sunitinib and the mTOR inhibitor everolimus. Show less
Renal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs.... Show moreRenal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs. Renal clearance includes glomerular filtration, tubular secretion and reabsorption and each of these processes is subject to different developmental changes. To estimate the renal clearance of drugs in children, a thorough understanding of these developmental changes in the different subprocesses contributing to renal function is needed. Therefore the aim of the research described in this thesis was to characterize the developmental changes in renal function over the entire pediatric age range. To this end, a system-based pharmacology approach was applied implicating that within the models for the different subprocesses contributing to renal function a distinction was made between system-specific and drug-specific properties. The transition to a more system-based pharmacology approach and the combination of different strategies (extrapolation to other drugs, adult data or non-clinical data) will result in an approach focusing on the underlying system instead of focusing on the drugs and may facilitate development of pharmacokinetic models and evidence-based dosing regimens in the pediatric population. Show less
In the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid ... Show moreIn the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid (brainECF) concentrations is highly restricted in human. Therefore, unbound drug concentrations in human cerebrospinal fluid (CSF) are used as a surrogate for human brainECF concentrations. Due to qualitative and quantitative differences in processes that govern the pharmacokinetics (PK) of drugs in the brain, a generally applicable relationship between CSF concentrations and brainECF concentrations does not exist. The aim of the research presented in this thesis was to develop a preclinical brain distribution model, allowing the prediction of human brain target site concentrations on the basis of preclinical data. In order to be able to build a brain distribution model understanding of time-dependent (also non-steady state) kinetics of the unbound drug in brainECF and CSF is essential. To that end, systematic studies on the inter-relationship of plasma PK, blood-brain barrier (BBB) transport, blood-CSF barrier (BCSFB) transport and intra-brain distribution were performed in the rat by implantation of microdialysis probes at multiple brain sites in individual animals. Show less
