The majority of marketed drugs remain understudied in some patient populations such as pregnant women, paediatrics, the obese, the critically-ill, and the elderly. As a consequence, currently used... Show moreThe majority of marketed drugs remain understudied in some patient populations such as pregnant women, paediatrics, the obese, the critically-ill, and the elderly. As a consequence, currently used dosing regimens may not assure optimal efficacy or minimal toxicity in these patients. Given the vulnerability of some subpopulations and the challenges and costs of performing clinical studies in these populations, cutting-edge approaches are needed to effectively develop evidence-based and individualized drug dosing regimens. Five key issues are presented that are essential to support and expedite the development of drug dosing regimens in these populations using model-based approaches: 1) model development combined with proper validation procedures to extract as much valid information from available study data as possible, with limited burden to patients and costs; 2) integration of existing data and the use of prior pharmacological and physiological knowledge in study design and data analysis, to further develop knowledge and avoid unnecessary or unrealistic (large) studies in vulnerable populations; 3) clinical proof-of-principle in a prospective evaluation of a developed drug dosing regimen, to confirm that a newly proposed regimen indeed results in the desired outcomes in terms of drug concentrations, efficacy, and/or safety; 4) pharmacodynamics studies in addition to pharmacokinetics studies for drugs for which a difference in disease progression and/or in exposure-response relation is anticipated compared to the reference population; 5) additional efforts to implement developed dosing regimens in clinical practice once drug pharmacokinetics and pharmacodynamics have been characterized in special patient populations. The latter remains an important bottleneck, but this is essential to truly realize evidence-based and individualized drug dosing for special patient populations. As all tools required for this purpose are available, we have the moral and societal obligation to make safe and effective pharmacotherapy available for these patients too. Show less
Aims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed... Show moreAims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model in both critically ill children and other populations in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was externally evaluated in 136 individuals, including (pre)term neonates, infants, children, and adults (body weight 0.77-90 kg, CRP 0.1-341 mg/L and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in post-operative or critically ill paediatric patients and term neonates (median prediction error (MPE) <30%). Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation, and organ failure in children yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children, and adults with varying levels of critical illness including healthy adults, but not for extrapolation to preterm neonates. 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
Interspecies translation of pharmacological processes needs to improve to reduce attrition in drug development. Systems pharmacology integrates systems biology and pharmacometrics to characterise... Show moreInterspecies translation of pharmacological processes needs to improve to reduce attrition in drug development. Systems pharmacology integrates systems biology and pharmacometrics to characterise and quantify system-specific behaviour upon exposure to drugs in different species. The zebrafish is a suitable vertebrate model organism for systems pharmacology, combining high-throughput potential with high genetic homology to higher vertebrates. Zebrafish larvae have been increasingly used for drug screens, but the influence of internal drug and metabolite exposure is hardly studied. Quantifying this internal exposure is essential for establishing both exposure-response and dose-exposure relationships, needed for translation. The zebrafish may also serve as a suitable model species for translational studies on the occurrence of hepatotoxicity and the influence of hepatic dysfunction on drug metabolism. Show less
Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic... Show moreAllometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age. Show less
Pain cannot be directly measured in neonates. Therefore, scores based on indirect behavioural signals such as crying, or physiological signs such as blood pressure, are used to quantify neonatal... Show morePain cannot be directly measured in neonates. Therefore, scores based on indirect behavioural signals such as crying, or physiological signs such as blood pressure, are used to quantify neonatal pain both in clinical practice and in clinical studies. The aim of this study was to determine which of the physiological and behavioural items of 2 validated pain assessment scales (COMFORT and premature infant pain profile) are best able to detect pain during endotracheal and nasal suctioning in ventilated newborns. We analysed a total of 516 PIPP and COMFORT scores from 118 newborns. A graded response model was built to describe the data and item information was calculated for each of the behavioural and physiological items. We found that the graded response model was able to well describe the data, as judged by agreement between the observed data and model simulations. Furthermore, a good agreement was found between the pain estimated by the graded response model and the investigator-assessed visual analogue scale scores (Spearman rho correlation coefficient = 0.80). The information scores for the behavioural items ranged from 1.4 to 27.2 and from 0.0282 to 0.131 for physiological items. In these data with mild to moderate pain levels, behavioural items were vastly more informative of pain and distress than were physiological items. The items that were the most informative of pain are COMFORT items "calmness/agitation," "alertness," and "facial tension." Show less
OBJECTIVE:To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome.DESIGN:Prospective, single-center... Show moreOBJECTIVE:To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome.DESIGN:Prospective, single-center observational trial.SETTING:PICU in a university-affiliated pediatric teaching hospital.PATIENTS:Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass.INTERVENTIONS:A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis.MEASUREMENTS AND MAIN RESULTS:Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 μg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 μg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome.CONCLUSIONS:This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome. Show less
INTRODUCTION In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of... Show moreINTRODUCTION In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice. Strategies should be developed to ensure that formularies update their drug dosing guidelines regularly according to the most recent advances in research, allowing for clinicians to integrate these guidelines in daily practice. Expert commentary: We anticipate a trend towards a systems-level approach in pediatric modeling to optimally use the information gained in pediatric trials. For this approach, properly designed clinical PKPD studies will remain the backbone of pediatric research. Show less
The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was... Show moreThe maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-based pharmacokinetic modeling it was concluded that the equation for maturation of morphine glucuronidation could be applicable to all small molecular drugs and to paediatric patient populations with normal hepatic function. Finally, a framework was developed to properly validate paediatric pharmacokinetic population models and the validation of paediatric pharmacokinetic models for morphine in literature were investigated. Show less
Krekels, E.H.J.; Neely, M.; Panoilia, E.; Tibboel, D.; Capparelli, E.; Danhof, M.; ... ; Knibbe, C.A.J. 2012
