This dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded... Show moreThis dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded matter. Unblinding might partially mitigate the limitation, but current measurement methods have gaps that we should remain aware of. Detailed measurements of subintervals with characterization of ion channel profiles, concentration QTc modelling, or machine learning might help physicians in their decision making in the future. Show less
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
Sepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global... Show moreSepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global healthcare systems. Bacterial infections are the primary cause of sepsis, but the growing prevalence of antimicrobial resistance complicates the effectiveness of antimicrobial treatments. Moreover, limited understanding of the host immune response during sepsis hinders the discovery of valuable biomarkers and drug targets. As such, there is an urgent need to improve the treatment of sepsis. To tackle this challenge, we have concentrated our efforts on optimizing current treatment strategies and on facilitating the discovery of novel host inflammatory response directed therapeutics. In this thesis, we have utilized quantitative pharmacological modeling approaches to assess the adequacy of current dose regimens and to evaluate antibiotic pharmacokinetic variability, thereby optimizing antimicrobial therapies for sepsis. Additionally, our researches had aimed to deepen our understanding of the underlying dynamics of sepsis pathology, enabling the identification of promising biomarkers and therapeutic targets for sepsis. Our work demonstrated how quantitative modeling strategies can support the design of optimized treatment strategies, and how systematic model-based integration of disease mechanisms can help to overcome the translational challenges in sepsis drug development. Show less
Background The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of... Show moreBackground The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. Methods Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). Results Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. Conclusions Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands. Show less
Aim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic... Show moreAim: In the registration trial, cabozantinib exposure >= 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care. Methods: Cabozantinib trough concentrations (C-min) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C-min > 750 ng/mL and median C-min. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. Results: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C-min was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C-min >= 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C-min >= 750 ng/mL or >= 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. >= 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004). Conclusion: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy. Show less
The last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in... Show moreThe last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in special patient populations where there is only limited guidance on how to optimally use opioids. In this thesis we focused on the perioperative use of opioids in three different populations. First, the influence of the opioids remifentanil versus fentanyl on acute and chronic postoperative pain was investigated in adult cardiac surgery patients. Second, pharmacodynamic modelling methods were applied to analyze the postoperative use of morphine in children after cardiac surgery. Finally, a pharmacokinetic model was developed to investigate the influence of obesity on the pharmacokinetics of morphine and its metabolites. Pain remains a complex puzzle among biological, psychological, behavioral and social-cultural factors. The high inter-individual variation in all of these factors results in postoperative pain still being a major issue while the ultimate goal is to stay without pain after a surgical procedure. Therefore, the answer to the question: “Does it still hurt?” is: YES unfortunately. This thesis adds pieces to this complex puzzle by focusing on the use of opioids in three different patient populations. 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 thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread... Show moreThe thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread targets in the nervous system can be expected to affect numerous CNS functions, which requires multimodal characterisation of pain processing and neurocognition. This is illustrated on the basis of two case studies of pharmacological agents that target cannabinoid CB1 and GABA-ergic GABAA receptors: two of the most widely distributed systems of receptors and neurotransmitters that are involved in a myriad of physiological functions. The distribution of receptors throughout the central nervous system render an oral formulation of ∆9-THC and a positive allosteric modulator of α2/3/5 subunit-containing GABAA receptors, ideal candidates for extensive neurophysiological and analgesic effect profiling in early phase clinical research. Profiling human pharmacology with a strong focus on pharmacodynamics may help to better understand the therapeutic potential and safety limitations of a compound before selection of doses and patient populations for phase II proof-of-concept studies. Show less
Background: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic... Show moreBackground: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%integral T > 1-4xMIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.Methods: This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (integral T > MICECOFF and integral T > 4xMIC(ECOFF)) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.Results: A total of 147 patients were included, of whom 63.3% achieved PDT of 100% integral T > MICECOFF and 36.7% achieved 100% integral T > 4xMIC(ECOFF). Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) >= 90 mL/min/1.73 m(2), and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100% integral T > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Show less
Despite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds... Show moreDespite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds with fewer side effects is therefore essential. With an increased demand to demonstrate pharmacodynamic effects of new analgesic compounds, the importance of human evoked pain models is now higher than ever. Pharmacodynamic evaluation with human evoked pain models offers the possibility to determine the dose ranges at which new analgesics exert their pharmacological effect. Pain models may also aid in the choice of target population, determine which modality of pain a new drug is expected to be most suitable, help to differentiate between a central or more peripheral mode of action of new drugs, and help determine which other effects contribute to its mode of action e.g., sedation. Using pain models in healthy volunteers has important advantages over assessing the effects of new drugs in patients with pain; the pain elicited in human pain models is predictable in its intensity while clinical pain will naturally fluctuate. Analgesic properties can be investigated with pain models without the influence of accompanying symptoms that are often seen in patients with pain. Show less
Muehlan, C.; Brooks, S.; Zuiker, R.; Gerven, J. van; Dingemanse, J. 2019
ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation,... Show moreACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median t(max) of 1.0-2.0 h across the 3 dose groups. The geometric mean elimination half-life (t(1/2)) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia. (C) 2019 Elsevier B.V. and ECNP. All rights reserved. Show less
Drug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target... Show moreDrug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target population. This is particularly appropriate for human pain where models can assist to bridge the preclinical and clinical findings. These models can provide valuable information about the mechanism of action of existing and new drugs. However, a single human pain model cannot be used exclusively to screen the pharmacological mechanism of a compound as it inherently only tests a single mechanism. In this thesis the performance of a battery of pain models (PainCart) was investigated. Three main topics were investigated. (1) The validation of the PainCart was described in which the effects of different classes of analgesics on this battery of pain models were explored. (2) The PainCart was used in different chronic pain populations. (3) The performance of the battery during the development of new analgesic compounds was studied. The battery of pain models can act as biomarker to assess the effect of analgesics on pain. It can be used to benchmark analgesic properties of new drugs against established analgesics in early phase clinical studies. Show less
This thesis concerns five studies where the statistical consequences of violations of modeling assumptions are assessed using experimental and simulated pharmacokinetic-pharmacodynamic data. The... Show moreThis thesis concerns five studies where the statistical consequences of violations of modeling assumptions are assessed using experimental and simulated pharmacokinetic-pharmacodynamic data. The first study describes the development of an open source web application for Bland-Altman analysis of comparison data, which is able to take into account both intra- and interindividual variability. In the second study the behavior of Akaike's information theoretic criterion is investigated in the presence of interindividual variability. The effects of neglecting or allowing for process noise are described in the third and fourth studies, for surrogate measures of clinical endpoints such depth of anesthesia and analgesia. In the fifth study pharmacodynamic model parameter estimates are compared when these are based on venous versus arterial blood samples. Show less
Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The... Show morePersonalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients’ (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future. Show less
Many physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations... Show moreMany physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations over the course of the day and night. This may lead to time-of-day dependent changes in the exposure and effect of therapeutic drugs. The aim of this thesis is to provide a structured framework for chronopharmacological studies, while concurrently touching upon several critical issues encountered during the development and optimization of new and existing drug treatments. Firstly, we studied 24-hour variation in the pharmacokinetics of both midazolam and levofloxacin in healthy male subjects and found that for both drugs, absorptive processes show time-of-day dependency. Moreover, the magnitude of QT prolongation induced by levofloxacin, a common side-effect induced by many types of drugs, varied considerably and systematically over the course of the day. Furthermore, we investigated daily variation of drug distribution to the brain and found that time of day can be a considerable source of variation that could influence the effectiveness of drugs targeted to the brain. Taken together, these studies show that chronopharmacological aspects should not be overlooked in order to benefit from the systematic fluctuations in physiological processes during the development and optimization of drug treatments. Show less
This thesis describes the potential role of non-invasive measurement of pharmacokinetics (pk) and pharmacodynamics (pd) in the research and development of central nervous system (cns) stimulants or... Show moreThis thesis describes the potential role of non-invasive measurement of pharmacokinetics (pk) and pharmacodynamics (pd) in the research and development of central nervous system (cns) stimulants or depressants for children and adolescents. First, we evaluated the feasibility of using saliva as an alternative to plasma in two studies on psychostimulants (caffeine and methylphenidate). Second, neuropsychological and neurophysiological functions were measured longitudinally using the NeuroCart, a battery of tests developed at the Centre for Human Drug Research (chdr, Leiden, The Netherlands) that includes non-invasive tests for alertness, visuomotor coordination, motor control, memory, and subjective drug effects. Using a non-invasive approach, age-dependent differences in alcohol pk and pd were evaluated between healthy adolescents and adults. This thesis concludes with the report of two clinical trials that were designed to evaluate age-appropriate formulations of sedative drugs that have the potential for use in children. Show less
This thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that... Show moreThis thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; 2) facilitate the integration of historical evidence and thereby the translation of findings across species; and 3) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Nonlinear-mixed effects modelling is recommended as a tool to account for such requirements. Our goal was to explore the feasibility of a model-based approach to toxicology assessment and risk prediction in humans and, where possible, to compare the performance of this approach to traditional safety assessment approaches. The investigational plan of the thesis was divided into two sections where the development of methodology is followed by a case study with real data. A variety of analysis strategies and protocol designs are investigated where we set the constraint that proposals to deviate from existing protocols be minimal. We finally compile recommendations for protocol optimisation and data analysis/interpretation strategies to facilitate the implementation of model-based techniques in safety pharmacology and toxicology research Show less
De neurotransmitter dopamine speelt een essenti_le rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de... Show moreDe neurotransmitter dopamine speelt een essenti_le rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de ziekte van Parkinson, schizofrenie, drugsverslaving en hyperprolactinemie. De huidige farmacotherapeutische methoden om dopaminerge neurotransmissie te be_nvloeden, hebben slechts een beperkt effect op de symptomen, terwijl hinderlijke bijwerkingen kunnen optreden. Derhalve heeft verbetering van de farmacotherapie van deze ziekten een hoge prioriteit. De bevindingen van studies in dit proefschrift en followup studies tonen aan dat verbetering van de kinetiek van het geneesmiddel ter plaatse van de receptor en verbetering van de selectiviteit van het geneesmiddel veelbelovende strategie_n zijn. De resultaten van be_nvloeding van de controle mechanismen door tachykinines en gaba lijken vooralsnog minder therapeutisch nut op te leveren, maar geven wel indicaties voor biologische effecten die verder onderzoek verdienen. Deze onderzoekslijnen geven aan dat, ondanks de grote verscheidenheid aan beschikbare dopamine agonisten en antagonisten, de therapeutische mogelijkheden om dopamine neurotransmissie te be_nvloeden nog lang niet verzadigd zijn Show less
