A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age-dependent differences in absorption

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess...

Application of proteomics to understand maturation of drug metabolizing enzymes and transporters for the optimization of pediatric drug therapy

Drug disposition in children is different compared to adults. Growth and developmental change the processes involved in drug disposition and efficacy, including membrane transporters and drug metabolizing enzymes, but for many of these proteins, the exact changes have not been fully elucidated to date. Quantitative proteomics offers a solution...

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,...

Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing

OBJECTIVES: Decreasing 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...

Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children

Aims: Drug 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...

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,...

Proteomic analysis of the developmental trajectory of human hepatic membrane transporter proteins in the first three months of life

Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10...

Pediatric Mïcrodose and Microtracer Studies Using 14C in Europe

Important information gaps remain on the efficacy and safety of drugs in children. Pediatric drug development encounters several ethical, practical, and scientifîc chaflenges One barrier to the evaluation of medicines for children is a lack of Innovative methodologies that have been adapted to the needs of chiIdren This article presents our...

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...

In vitro gastrointestinal model (TIM) with predictive power, even for infants and children?

There is a need for information on the bioavailability in pediatric patients of drugs from manipulated dosage forms when applied in combination with food and/or co-medication under realistic daily practice circumstances. We describe the development, validation and application of a dynamic, computer-controlled in vitro system mimicking the...