Review: Ontogeny of oral drug absorption processes in children

A large proportion of prescribed drugs to children are administered orally. Age-related change in factors affecting oral absorption can have consequences for drug dosing. Areas covered: For each process affecting oral drug absorption, a systematic search has been performed using Medline to identify relevant articles (from inception till February 2012) in humans. This review presents the findings on age-related changes of the following processes affecting oral drug absorption: gastric pH, gastrointestinal motility, bile salts, pancreatic function, intestinal pH, intestinal drug-metabolizing enzymes and transporter proteins. Expert opinion: Clinicians should bear in mind the ontogeny of oral drug absorption processes when prescribing oral drugs to children. The authors’ review shows large information gaps on almost all drug absorption processes. It is important that more knowledge is acquired on intestinal transit time, intestinal pH and the ontogeny of intestinal drug-metabolizing enzymes and drug transporter proteins. Furthermore, the ultimate goal in this field should be to predict more precisely the oral disposition of drugs in children across the entire pediatric age range

Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics

Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug–drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children

A randomized controlled trial of daily sedation interruption in critically ill children

Purpose: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. Methods: 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. Results: 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. Conclusion: 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

Proof of Concept: First Pediatric [14C]microtracer Study to Create Metabolite Profiles of Midazolam

Growth and development affect drug-metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive burden. To overcome this challenge, we aimed to show the feasibility of an absorption, distribution, metabolism, and excretion (ADME) study using a [(14) C]midazolam microtracer as proof of concept in children. Twelve stable, critically ill children received an oral [(14) C]midazolam microtracer (20 ng/kg; 60 Bq/kg) while receiving intravenous therapeutic midazolam. Blood was sampled up to 24 hours after dosing. A time-averaged plasma pool per patient was prepared reflecting the mean area under the curve plasma level, and subsequently one pool for each age group (0-1 month, 1-6 months, 0.5-2 years, and 2-6 years). For each pool [(14) C]levels were quantified by accelerator mass spectrometry, and metabolites identified by high resolution mass spectrometry. Urine and feces (n = 4) were collected up to 72 hours. The approach resulted in sufficient sensitivity to quantify individual metabolites in chromatograms. [(14) C]1-OH-midazolam-glucuronide was most abundant in all but one age group, followed by unchanged [(14) C]midazolam and [(14) C]1-OH-midazolam. The small proportion of unspecified metabolites most probably includes [(14) C]midazolam-glucuronide and [(14) C]4-OH-midazolam. Excretion was mainly in urine; the total recovery in urine and feces was 77-94%. This first pediatric pilot study makes clear that using a [(14) C]midazolam microtracer is feasible and safe to generate metabolite profiles and study recovery in children. This approach is promising for first-in-child studies to delineate age-related variation in drug metabolite profiles

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Background: We previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP). Methods: Infants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolit

Daily interruption of sedation in critically ill children: Study protocol for a randomized controlled trial

Background: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and

Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively.Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children

Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants

Background: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. Methods: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. Results: We analyzed 36 fetal (median GA 23.4 weeks [range 15.3–41.3]), 12 premature newborn (GA 30.2 weeks [24.9–36.7], PNA 1.0 weeks [0.14–11.4]), 10 term newborn (GA 40.0 weeks [39.7–41.3], PNA 3.9 weeks [0.3–18.1]), 4 pediatric (PNA 4.1 years [1.1–7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. Discussion and conclusion: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge

Benefit-Risk Assessment of Off-Label Drug Use in Children

A drug is granted a license for use after a thorough assessment of risks and benefits based on high-quality scientific proof of its efficacy and safety. Many drugs that are relevant to children are not licensed for use in this population implying that a thorough assessment of risks and benefits in the pediatric population has not been made at all, implying a negative risk-benefit balance in children, or implying insufficient information to establish the risk-benefit balance. Use of drugs without positive assessment of risks and benefits exposes children to potential lack of efficacy, unknown toxicity, and harm. To aid guideline committees and individual prescribers, we here present a tutorial of the Benefit and Risk Assessment for Off-label use (BRAvO) decision framework. This pragmatic framework offers a structured assessment of benefits and risks of off-label drug use, including a clinical pharmacological based approach to age-appropriate dose selection. As proof of concept and to illustrate the practical use, we have applied the framework to assess benefits and risks of off-label use of ondansetron for gastroenteritis-induced nausea and vomiting. The framework could also guide decisions on off-label use in other special populations (e.g., pregnant women, elderly, obese, or critically ill patients) where off-label drug use is frequent, thereby contributing to effective and safe pharmacotherapy.</p