Aims and Scope: For more than 50 years, clinical pharmacologists, clinical and pharmaceutical researchers, drug development specialists, physicians, nurses, and other medical professionals have relied on The Journal of Clinical Pharmacology (JCP) for original research, special reviews, commentaries, and case reports on all phases of drug development from absorption, disposition, metabolism, excretion interactions, and preferred uses through post-marketing evaluations.
Drug metabolism importantly determines drug concentrations. The efficacy and safety of many drugs prescribed for children are, therefore, dependent on intraindividual and interindividual variation in drug-metabolising enzyme activity. During growth and development, changes in drug-metabolising enzyme activity result in age-related differences in drug disposition, most pronounced in preterm infants and young infants. The shape of the developmental trajectory is unique to the drug-metabolising enzyme involved in the metabolism of individual drugs. Other factors impacting drug metabolism are underlying disease, drug–drug interactions and genetic variation. The interplay of age with these other factors may result in unexpected variation in drug metabolism in children of different ages. Extrapolation of adult data to guide drug dosing in children should be done with caution. The younger the child, the less reliable is the extrapolation. This review aims to identify the primary sources of variability of drug metabolism in children, the knowledge of which can ultimately guide the practitioner towards effective and safe drug therapy.
To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children.In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient's sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the 'open' infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat.From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6-25.8) versus PS 24.0 days (IQR 20.6-26.0); median difference 0.02 days (95 % CI -0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2-11.0) versus PS 7.4 days (IQR 5.3-12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6-26.7) versus PS 15.7 days (IQR 9.3-33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6-22.6) versus PS 17.0 mg/kg (IQR 8.2-39.8), p = 0.11.In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only.
Background The kidney has a critical role in disposition, efficacy and toxicity of drugs and xenobiotics. Developmental changes of renal membrane transporters have the potential to explain population variability in paediatric pharmacokinetics and -dynamics of drugs but data are missing. We aimed to further delineate the expression of human renal tubular transporters multidrug resistance-associated protein (MRP) 4 and MRP2 and study localization in paediatric kidney samples. Methods We planned to semi-quantify expression levels and to study the age-specific localization of the transporters MRP4 and MRP2 with immunohistochemistry on 44 human neonatal and paediatric kidney samples with age range of 24,00 - 40,00 weeks gestational age (GA) and 0,29 - 744 weeks post-natal age (PNA). The staining intensity was semi-quantitatively scored by two independent observers (MB and BG). Results MRP4 is found to be localized at the apical membrane of the renal proximal tubules at 27 weeks of GA (n=3, 1,29- 4 weeks PNA) and no age-related changes of expression levels were detected. In a premature neonate of 24 weeks GA (n=1), no MRP4 was detected. The MRP2 staining did not meet the requirements to be scored and was rejected. Conclusion MRP4 is expressed from at least 27 weeks GA onwards and does not show developmental changes. The localization was similar as in adults (Ritter et al., 2005). The half-life of the MRP4 substrate furosemide was found to be 6 to 20-fold longer in neonates than in adults (Pacifici, G.M., 2013). This could potentially be linked with the absence of MRP4 in a premature neonate with GA 24 weeks. However, these data should be confirmed as we only had 1 sample of ±24 weeks GA available. Moreover, our data help us in understanding altered disposition of transporter substrates in paediatrics. References Pacifici, G. M. ( 2013). Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals ;6(9):1094–1129. Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Köck K, & Kroemer HK. ( 2005). Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews ;37(1):253–278. Disclosure(s) Nothing to disclose
Physiologically based pharmacokinetic (PBPK) modeling can be an attractive tool to increase the evidence base of pediatric drug dosing recommendations by making optimal use of existing pharmacokinetic (PK) data. A pragmatic approach of combining available compound models with a virtual pediatric physiology model can be a rational solution to predict PK and hence support dosing guidelines for children in real-life clinical care, when it can also be employed by individuals with little experience in PBPK modeling. This comes within reach as user-friendly PBPK modeling platforms exist and, for many drugs and populations, models are ready for use. We have identified a list of drugs that can serve as a starting point for pragmatic PBPK modeling to address current clinical dosing needs.
As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID‐19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best‐evidence to inform pediatric CHQ doses for children infected with COVID‐19. A previously developed physiologically‐based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID‐19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration‐time curve from zero to 70 hours (AUC 0–70h ) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re‐introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body‐weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0–1 month, 47 mg/kg for 1–6 months, 55 mg/kg for 6 months–12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age‐adjusted CHQ dosing in children with COVID‐19 in order to avoid suboptimal or toxic doses. The knowledge‐driven, model‐informed dose selection paradigm can serve as a science‐based alternative to recommend pediatric dosing when pediatric clinical trial data is absent.
