While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration... Show moreWhile the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children. Show less
For the management of iatrogenic withdrawal syndrome (IWS) in children, a quantitative understanding of the dynamics of IWS of commonly used opioids and sedatives is lacking. Here, we introduce a... Show moreFor the management of iatrogenic withdrawal syndrome (IWS) in children, a quantitative understanding of the dynamics of IWS of commonly used opioids and sedatives is lacking. Here, we introduce a new mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling approach for studying IWS in pediatric clinical datasets. One thousand seven hundred eighty-two NRSwithdrawal scores of IWS severity were analyzed, which were collected from 81 children (age range: 1 month-18 years) that received opioids or sedatives by continuous infusion for 5 days or more. These data were successfully fitted with a PKPD model consisting of a plasma and a dependence compartment that well characterized the dynamics of IWS from morphine, fentanyl, and ketamine. The results suggest that (1) instead of decreasing the infusion rate by a set percentage at set intervals, it would be better to lengthen the weaning period when higher infusion rates are administered prior to weaning; (2) for fentanyl specifically, the risk of IWS might be lower when weaning with smaller dose reductions every 12 h instead of weaning with greater dose reductions every 48 h. The developed PKPD model can be used to evaluate the risk of IWS over time and the extent to which it is affected by different weaning strategies. The results yield hypotheses that could guide future clinical research on optimal weaning strategies. The mechanism-based PKPD modeling approach can be applied in other datasets to characterize the IWS dynamics of other drugs used in pediatric intensive care. Show less
Cristea, S.; Krekels, E.H.J.; Allegaert, K.; Paepe, P. de; Jaeger, A. de; Cock, P. de; Knibbe, C.A.J. 2021
To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic ... Show moreTo date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL(R)post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within +/- 50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters. Show less
Hoogd, S. de; Goulooze, S.C.; Valkenburg, A.J.; Krekels, E.H.J.; Dijk M. van; Tibboel, D.; Knibbe, C.A.J. 2021
Background Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine.... Show moreBackground Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine. Methods Data on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 mu g kg(-1)) with continuous infusion (40 mu g kg(-1) h(-1)) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling. Results During the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml(-1) (range 7-180 ng ml(-1)). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml(-1)) increased at higher morphine concentrations (P < 0.001). Conclusions In this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children. ImpactIn children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children. Show less
Hartman, S.; Upadhyay, P.; Hagedoorn, N.; Krekels, E.H.J.; Mathot, R.; Moll, H.; ... ; Wildt, S. de 2021
Background and Purpose There is a clear need for innovation in anti-tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate... Show moreBackground and Purpose There is a clear need for innovation in anti-tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate pharmacological findings to higher vertebrates, including humans, the internal exposure of drugs needs to be quantified and linked to observed response.Experimental Approach In zebrafish studies, drugs are usually dissolved in the external water, posing a challenge to quantify internal exposure. We developed experimental methods to quantify internal exposure, including nanoscale blood sampling, and to quantify the bacterial burden, using automated fluorescence imaging analysis, with isoniazid as the test compound. We used pharmacokinetic-pharmacodynamic modelling to quantify the exposure-response relationship responsible for the antibiotic response. To translate isoniazid response to humans, quantitative exposure-response relationships in zebrafish were linked to simulated concentration-time profiles in humans, and two quantitative translational factors on sensitivity to isoniazid and stage of infection were included.Key Results Blood concentration was only 20% of the external drug concentration. The bacterial burden increased exponentially, and an isoniazid dose corresponding to 15 mg center dot L(-1)internal concentration (minimum inhibitory concentration) leads to bacteriostasis of the mycobacterial infection in the zebrafish. The concentration-effect relationship was quantified, and based on that relationship and the translational factors, the isoniazid response was translated to humans, which correlated well with observed data.Conclusions and Implications This proof of concept study confirmed the potential of zebrafish larvae as tuberculosis disease models in translational pharmacology and contributes to innovative anti-tuberculosis drug development, which is very clearly needed. Show less
BACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nOptimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both... Show moreBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nOptimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery.\nThe rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4).\nPatients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL (95% CI, 6.7-16).\nThe pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed. Show less
Objectives: This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and... Show moreObjectives: This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing.Design: Retrospective pilot population pharmacokinetic analysis.Setting: Neonatal ICU.Patients: Thirteen critically ill neonates (birth body weight, 3.21kg [2.65-3.72 kg]; postnatal age at start of treatment: 2 d [0-7 d]; gestational age: 38wk [38-41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation.Interventions: Phenobarbital administered in a loading dose of 7.5mg/kg (8.5-16mg/kg) and maintenance dose of 6.9mg/kg/d (4.5-8.5mg/kg/d).Measurements and Main Results: Therapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21kg) at median postnatal age (2 d) were 0.0096L/hr (relative se = 11%)) and 2.72L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20mg/kg and a maintenance dose of 4mg/kg/d divided in two doses with an increase of 0.25mg/kg every 12 hours during extracorporeal membrane oxygenation treatment.Conclusions: We found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen. Show less
Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet... Show moreMidazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1-OH-midazolam (OHM) and 1-OH-midazolam-glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [C-14]midazolam microtracer population pharmacokinetic study. Forty-six stable, critically ill children (median age 9.8 (range 0.3-276.4) weeks) received a single oral [C-14]midazolam microtracer (58 (40-67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one-compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25-85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49-92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A-substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity. Show less
Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we... Show moreGlomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CL(R)for drugs with different properties in children. A physiology-based model for CL(R)in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hypothetical drugs with a range of drug-specific properties, including transporter-mediated intrinsic clearance (CLint,T) values, that are substrates for renal secretion transporters with different ontogeny patterns. To assess the impact of transporter ontogeny on ATS and total CLR, a percentage prediction difference (%PD) was calculated between the predicted CL(R)in the presence and absence of transporter ontogeny. The contribution of ATS to CL(R)ranges between 41 and 90% in children depending on fraction unbound and CL(int,T)values. If ontogeny of renal transporters is < 0.2 of adult values, CL(R)predictions are unacceptable (%PD > 50%) for the majority of drugs regardless of the pediatric age. Ignoring ontogeny patterns of secretion transporters increasing with age in children younger than 2 years results in CL(R)predictions that are not systematically acceptable for all hypothetical drugs (%PD > 50% for some drugs). This analysis identified for what drug-specific properties and at what ages the contribution of ATS on total pediatric CL(R)cannot be ignored. Drugs with these properties may be sensitivein vivoprobes to investigate transporter ontogeny. Show less
Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study... Show moreTitrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case-by-case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks. Show less
Introduction For drugs eliminated by glomerular filtration (GF), clearance (CL) is determined by GF rate (GFR) and the unbound fraction of the drug. When predicting CL of GF-eliminated drugs in... Show moreIntroduction For drugs eliminated by glomerular filtration (GF), clearance (CL) is determined by GF rate (GFR) and the unbound fraction of the drug. When predicting CL of GF-eliminated drugs in children, instead of physiologically based pharmacokinetic (PBPK) methods that consider changes in both GFR and protein binding, empiric bodyweight-based methods are often used. In this article, we explore the predictive value of scaling using a GFR function, and compare the results with linear and allometric scaling methods for drugs with different protein-binding properties. Methods First, different GFR maturation functions were compared to identify the GFR function that would yield the most accurate GFR predictions across the pediatric age range compared with published pediatric inulin/mannitol CL values. Subsequently, the accuracy of pediatric CL scaling using this GFR maturation function was assessed and compared with PBPK CL predictions for hypothetical drugs binding, to varying extents, to serum albumin or alpha-acid glycoprotein across the pediatric age range. Additionally, empiric bodyweight-based methods were assessed. Results The published GFR maturation functions yielded comparable maturation profiles, with the function reported by Salem et al. leading to the most accurate predictions. On the basis of this function, GFR-based scaling yields reasonably accurate (percentage prediction error <= 50%) pediatric CL values for all drugs, except for some drugs highly bound to AGP in neonates. Overall, this method was more accurate than linear or 0.75 allometric bodyweight-based scaling. Conclusion When scaling CL and dose by GFR function, maturational changes in plasma protein concentrations impact GF minimally, making this method a superior alternative to empiric bodyweight-based scaling. Show less
Wijk, R.C. van; Sar, A.M. van der; Krekels, E.H.J.; Verboom, T.; Spaink, H.P.; Simonsson, U.S.H.; Graaf, P.H. van der 2020
The zebrafish infected with Mycobacterium marinum is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis infections in humans. To translate... Show moreThe zebrafish infected with Mycobacterium marinum is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and MUSA, is studied over an extended period using an established model‐based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm‐derived strain E11 and human‐derived strain MUSA were grown undisturbed up to 221 days and viability of cultures (CFU/mL) was determined by plating at different time points. Non‐linear mixed effects modelling using the MTP model quantified the bacterial growth, the transfer between fast‐, slow‐, and non‐multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20‐25 days for E11 and MUSA, respectively, followed by a decrease to a new plateau. Natural growth of both E11 and MUSA was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow‐multiplying state, for MUSA in the fast‐multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, while MUSA showed more aggressive growth behaviour. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of anti‐tuberculosis drug development. Show less
Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect... Show morePharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials. Show less
Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study... Show moreTitrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P Show less
Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral... Show moreMicrotracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief.\nDecreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue.\nAn innovative microtracer study design with population pharmacokinetics.\nA tertiary referral PICU.\nStable critically ill children, 0-6 years old, and already receiving IV acetaminophen.\nConcomitant administration of an oral C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr).\nBlood was drawn from an indwelling arterial or central venous catheter up to 24 hours after C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C concentrations by accelerated mass spectrometry.\nIn 47 patients (median age of 6.1 mo; Q1-Q3, 1.8-20 mo) the mean enteral bioavailability was 72% (range, 11-91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. Show less
Despite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from... Show moreDespite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from children by using real-world data from electronic health records, mobile applications, wearables, and social media. The large datasets collected with these approaches enable, and may demand, the use of artificial intelligence and machine learning to allow the data to be analyzed for decision-making. Applications of this approach are presented, which include the prediction of future clinical complications, medical image analysis, identification of new pediatric endpoints and biomarkers, the prediction of treatment non-responders and the prediction of placebo-responders for trial enrichment. Finally, we discuss how to bring machine learning from science to pediatric clinical practice. We conclude that advantage should be taken of the current opportunities offered by innovations in data science and machine learning to close the pediatric evidence gap. Show less
Groen, B.D. van; Vaes, W.H.; Park, B.K.; Krekels, E.H.J.; Duijn, E. van; Körgvee, L.-T.; ... ; Turner, M.A. 2019
AimsDrug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however... Show moreAimsDrug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [14C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose.MethodsPreterm to 2‐year‐old infants admitted to the intensive care unit received [14C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [14C]midazolam and [14C]1‐hydroxy‐midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed.ResultsOf 15 infants (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), 6 received a microtracer and 9 a microdose of [14C]midazolam (111 Bq kg−1; 37.6 ng kg−1). In a 2‐compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [14C]1‐OH‐midazolam/[14C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses.ConclusionOur data support the dose linearity of the PK of an IV [14C]midazolam microdose in children. Hence, a [14C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. Show less
Item-level data from composite scales can be analyzed with pharmacometric item response theory (IRT) models to improve the quantification of disease severity compared with the use of total... Show moreItem-level data from composite scales can be analyzed with pharmacometric item response theory (IRT) models to improve the quantification of disease severity compared with the use of total composite scores. However, regular IRT models assume unidimensionality, which is violated in the scale measuring iatrogenic withdrawal in children because some items are also affected by pain, undersedation, or delirium. Here, we compare regular IRT modelling of pediatric iatrogenic withdrawal symptom data with two new analysis approaches in which the latent variable is guided towards the condition of interest using numerical withdrawal severity scored by nurses as a "supervising variable": supervised IRT (sIRT) and supervised multi-dimensional (smIRT) modelling. In this example, in which the items scores are affected by multiple conditions, regular IRT modeling is worse to quantify disease severity than the total composite score, whereas improved performance compared with the composite score is observed for the sIRT and smIRT models. Show less
