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
Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health.... Show moreFungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health. Maximizing the effectiveness of existing antifungal drugs is imperative. Among these, fluconazole and posaconazole are commonly prescribed to treat severe and life-threatening fungal infections. In this thesis, among others, we aimed to understand better how well different posaconazole formulations are absorbed. Through computational modeling and simulation, we learned that posaconazole is best taken with food to reduce the risk of inadequate drug absorption and subsequent therapeutic failure. This applies not only to the suspension but also to the tablet, which results in higher and more predictable absorption even though it does not achieve concentrations similar to those upon intravenous administration. Fluconazole was studied in individuals with obesity. Our findings indicate that heavier adult males may require a higher dose to achieve the desired exposure. Consequently, we proposed dosing recommendations for treating obese patients. In summary, this research, a result of the long-term collaboration between Leiden University and Radboudumc, enhanced our knowledge of factors that reduce exposure to antifungal drugs, allowing us to guide how to individualize and optimize antifungal treatment in individual patients. Show less
Molen, A.J. van der; Dekkers, I.A.; Geenen, R.W.F.; Bellin, M.F.; Bertolotto, M.; Brismar, T.B.; ... ; Clement, O. 2023
The pharmacokinetics of contrast media (CM) will determine how long safe waiting intervals between successive CT or MRI examinations should be. The Contrast Media Safety Committee has reviewed the... Show moreThe pharmacokinetics of contrast media (CM) will determine how long safe waiting intervals between successive CT or MRI examinations should be. The Contrast Media Safety Committee has reviewed the data on pharmacokinetics of contrast media to suggest safe waiting intervals between successive contrast-enhanced imaging studies in relation to the renal function of the patient. 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 Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC).... Show moreBackground Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4*22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. Methods Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. Findings From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC -present in 35% of patients- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/ AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). Interpretation ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osi-mertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. Show less
Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. ...Show moreObjective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies. 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
The prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho... Show moreThe prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho)physiological changes in obese individuals can influence drug pharmacokinetics, implying adjusted doses, there is still a need for specific dose guidelines for many classes of drugs. In this thesis, the pharmacokinetics of the renally cleared antibiotics gentamicin, tobramycin and vancomycin, drugs for which it is well known that both the efficacy and toxicity of these drugs closely relate to blood concentrations, are studied in non-obese and (morbidly) obese adults, adolescents and children. We present practical dose recommendations for the obese adult, paediatric and adolescent populations. Furthermore, some important questions are addressed regarding the pharmacokinetics of drugs in obesity: can we use the lipophilicity of a drug to predict changes in volume of distribution? Which pitfalls have to be considered when using lean body weight as basis for drug dosing? And which methods for estimating glomerular filtration can predict the clearance of renally cleared drugs in obese patients? The work in this thesis provide some important steps in filling the current knowledge gaps regarding the pharmacokinetics of drugs in obesity. Show less
A novel mathematical model describes spatial-temporal drug distribution within one or more brain units, which are cubic representations of a piece of brain tissue with brain capillaries at the... Show moreA novel mathematical model describes spatial-temporal drug distribution within one or more brain units, which are cubic representations of a piece of brain tissue with brain capillaries at the edges. The brain unit can be considered a highly representative building block of the brain in terms of drug distribution. While the focus of the model is on drug distribution within the brain ECF, the model includes descriptions of drug concentrations within the blood plasma, drug distribution via brain capillary blood flow, drug transport across the blood-brain barrier (BBB) by passive paracellular and transcellular transport as well as active transport, brain ECF diffusion, brain ECF bulk flow, non-specific binding of the drug to brain tissue, and drug target binding kinetics. We study the model with analytical methods and numerical simulations. This allows us to examine the integrated effect of the individual processes important to drug distribution and effect on the local concentration-time profiles of free and (non-)specifically bound drug. Moreover, the model allows us to generate a local distribution profile of a drug within the brain. In addition, the impact of disease-induced changes in brain-specific properties on the concentrations of drug within the brain ECF is assessed. Show less
Russo, F.M.; Mian, P.; Krekels, E.H.; Calsteren, K. van; Tibboel, D.; Deprest, J.; Allegaert, K. 2019
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
Growth and development affect the metabolism of drugs administered to neonates, infants, and children. Research in this thesis focused on the metabolism by cytochrome P450 (CYP) 3A enzymes, aiming... Show moreGrowth and development affect the metabolism of drugs administered to neonates, infants, and children. Research in this thesis focused on the metabolism by cytochrome P450 (CYP) 3A enzymes, aiming to predict CYP3A-mediated clearance in neonates, infants, and children, by development of pediatric (physiological) population pharmacokinetic models.CYP3A-mediated systemic metabolism of midazolam in critically ill pediatric patients was found to be impacted by body weight, critical illness, and inflammation. The developed model was subsequently found to accurately predict clearance in postoperative children or critically ill patients. Furthermore, advanced physiological modelling methods were applied to distinguish between first-pass and systemic CYP3A-mediated metabolism to elucidate the role of intestinal and hepatic CYP3A in neonates and children covering the whole pediatric age range. Lastly, it was described when a pediatric covariate function for CYP3A-mediated midazolam clearance could be applied to scale plasma clearance of other CYP3A substrates in the pediatric population.This work will significantly improve CYP3A-mediated clearance predictions in neonates, infants, and children, which will ultimately lead to rational support for pediatric doses of CYP3A substrates in first-in-child studies during drug development and for pediatric dose recommendations for CYP3A substrates in clinical practice. 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
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
