Prematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are... Show morePrematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are not necessarily similar to prematurely born neonates. When suboptimal dosing guidelines are applied the neonates are at risk for under- or overdosing. In this thesis the pharmacokinetics and pharmacodynamics of a variety of drugs frequently used in preterm neonates were characterized, ultimately to optimize treatment. Specifically, caffeine, ibuprofen and fluconazole were studied which are drugs to treat apnea of prematurity, to close a patent ductus arteriosus and to treat or prevent infections with Candida in newborns, respectively. These drugs were introduced and used in clinical practice without sufficient knowledge, especially on appropriate dosing for this subpopulation. For caffeine and ibuprofen we found that the clearance rapidly increases with postnatal age, while for fluconazole clearance is better reflected by body weight and serum creatinine. For these drugs dosing guidelines were proposed based on identified covariates for their pharmacokinetics. Ibuprofen therapy was further investigated by examining the course of spontaneous closure of the ductus arteriosus, and evaluating the effects of ibuprofen exposure and patient characteristics simultaneously. Show less
PHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a... Show morePHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a warning on the anti-seizure drug lamotrigine claiming that it has the potential to increase the risk of arrhythmias and related sudden cardiac death due to a pharmacological sodium channel-blocking effect. We hypothesized that the risk of ar-rhythmias and related death is due to toxicity. We used the PHARMACOM-EPI framework to investigate the relationship between lamotrigine's plasma concentrations and the risk of death in older patients using real-world data. Danish nationwide administrative and healthcare registers were used as data sources and individuals aged 65 years or older during the period 1996 - 2018 were included in the study. According to the PHARMACOM-EPI framework, plasma concentrations of lamotrigine were predicted at the time of death and patients were cate-gorized into non-toxic and toxic groups based on the therapeutic range of lamotrigine (3-15 mg/L). Over 1 year of treatment, the incidence rate ratio (IRR) of all-cause mortality was calculated between the propensities score matched toxic and non-toxic groups. In total, 7286 individuals were diagnosed with epilepsy and were exposed to lamotrigine, 432 of which had at least one plasma concentration measurement The pharmacometric model by Chavez et al. was used to predict lamotrigine's plasma concentrations considering the lowest absolute percentage error among identified models (14.25 %, 95 % CI: 11.68-16.23). The majority of lamotrigine associated deaths were cardiovascular-related and occurred among individuals with plasma concentrations in the toxic range. The IRR of mortality between the toxic group and non-toxic group was 3.37 [95 % CI: 1.44-8.32] and the cumulative incidence of all-cause mortality exponentially increased in the toxic range. Application of our novel framework PHARMACOM-EPI provided strong evidence to support our hypothesis that the increased risk of all-cause and cardiovascular death was associated with a toxic plasma concentration level of lamotrigine among older lamo-trigine users. Show less
Explaining treatment response variability between and within patients can support treatment and dosing optimization, to improve treatment of individual patients. This thesis discussed multiple... Show moreExplaining treatment response variability between and within patients can support treatment and dosing optimization, to improve treatment of individual patients. This thesis discussed multiple aspects of treatment variability and the associated statistical learning techniques which can be used to explain and/or predict part of that variability. Even though in recent times the availability of several high-throughput measurement technologies has created many new opportunities to develop improved treatment strategies, deriving actionable insights from such data remains a challenge. To this end, the use of longitudinal and high-dimensional data analysis techniques is needed to explore omics data for explaining treatment response and clinical course, and to answer clinical questions from routine healthcare data from hospitals and research institutes. Show less
Antimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment... Show moreAntimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment strategies in patients offers an important direction to address this challenge. In this thesis, we describe how quantitative characterisation of the drug, the pathogen, and the patients, and how these three factors interact, can help to achieve this goal. To this end, we used a combination of state-of-the-art in silico model-based approaches to analyse and integrate experimental data from in vitro models, and clinical data from healthy volunteers and patients. We developed models describing infection site drug exposure, antimicrobial resistance evolution, and host response biomarker dynamics. We explored the impact of infection on pulmonary pharmacokinetics, evolutionary-based treatment strategies, and the utility host response biomarker for treatment monitoring. The work in this thesis builds towards developing novel strategies to optimise antimicrobial treatments and showcases the importance on interdisciplinary collaborations. Show less
This thesis was aimed at optimizing immunosuppressive therapy in kidney transplant recipients using pharmacometric models. Kidney transplantation comprises the preferred treatment strategy for... Show moreThis thesis was aimed at optimizing immunosuppressive therapy in kidney transplant recipients using pharmacometric models. Kidney transplantation comprises the preferred treatment strategy for patients with end-stage kidney disease. Its clinical success is challenged by graft rejection, necessitating lifelong immunosuppressive therapy to accommodate host-graft adaptation. Herein, achievement of balanced immunosuppression is vital for optimal outcomes, but is complicated by pharmacokinetic variability of the immunosuppressants. Currently, therapeutic drug monitoring (TDM)-guided dose individualization is conducted in an effort to achieve immunosuppressant exposure with adequate rejection prophylaxis and minimal toxicity. However, TDM target attainment rates are low and graft rejection and toxicity are observed in patients with on-target immunosuppressant exposure, indicating a need for further improvement. Pharmacometrics harnesses options to modernize this endeavor, allowing for model-based prediction of individual pharmacokinetic behavior and dosage requirements from patient characteristics and pharmacokinetic observations. We reviewed the current state of pharmacometrics in kidney transplantation, developed pharmacometric models for alemtuzumab and iohexol, externally evaluated a model-based dosing tool for everolimus, and combined pharmacometrics with microsampling to enable remote monitoring of immunosuppressant exposure and kidney function, simultaneously. Our research underlines the broad applicability of pharmacometrics and provides an impulse for future research to further optimize immunosuppressive therapy in kidney transplantation. Show less
Zwart, T.C.; Guchelaar, H.J.; Boog, P.J.M. van der; Swen, J.J.; Gelder, T. van; Fijter, J.W. de; Moes, D.J.A.R. 2021
Immunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient... Show moreImmunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient and within-patient pharmacokinetic (PK) variability. This could warrant the application of personalised dosing strategies to optimise individual patient outcomes. Pharmacometrics, the science that investigates the xenobiotic-biotic interplay using computer-aided mathematical modelling, provides options to describe and quantify this PK variability and enables identification of patient characteristics affecting immunosuppressant PK and treatment outcomes. Here, we review and critically appraise the available pharmacometric model-informed dosing solutions for the typical immunosuppressants in modern renal transplantation, to guide their initial and subsequent dosing. Show less
Although ketamine can be considered to be an “old” drug, a definitive model explainingketamine pharmacokinetics for a wide range of patient populations, dosing regimens and ketamine administrations... Show moreAlthough ketamine can be considered to be an “old” drug, a definitive model explainingketamine pharmacokinetics for a wide range of patient populations, dosing regimens and ketamine administrations forms is lacking. Currently, a large number of ketamine population pharmacokinetic models is published. However, the large number of ketamine pharmacokinetic models based on data from all types of study populations,ketamine dosing regimens and administration forms, can prove to become a serious challenge for clinical decision makers, since it may not always be easy to pick the model that best suits their patient population. In this thesis, we focus on unraveling the complex pharmacokinetics and pharmacodynamics that characterize ketamine, in order to get a step closer to a final “all encompassing” pharmacokinetic-pharmacodynamic model. For the pharmacodynamic outcomes, we especially focus on the effects of ketamine on neuropathic pain, nociceptive pain (pressure pain) and psychedelic outcomes. Show less
The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors... Show moreThe aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen. Show less
This book focuses on novel approach to characterize developmental changes in pharmacokinetics across human lifespan with the up-to-date Nonlinear Mixed Effect Modeling techniques.
