Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults.

Beta adrenergic receptor antagonists, known as beta blockers, are one of the most prescribed medications in both pediatric and adult cardiology. Unfortunately, most of these agents utilized in the pediatric clinical setting are prescribed off-label. Despite regulatory efforts aimed at increasing pediatric drug labeling, a majority of pediatric cardiovascular drug agents continue to lack pediatric-specific data to inform precision dosing for children, adolescents, and young adults.

Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia.

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs.

Peak Oxygen Consumption (V̇O 2peak ) Recovery Delay in a Pediatric Fontan Population.

Purpose: The purpose of this study is to identify predictors and correlates of VO2RD in youth with Fontan.

Methods: Cardiopulmonary exercise test data was used from a single center, cross-sectional study of children and adolescents (age, 8-21 yr) with Fontan physiology. The VO2RD was determined using time (s) to <90% of V̇O 2peak and categorized as "low" (≤10 s) or "high" (≥10 s).

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.

PharmVar GeneFocus: SLCO1B1.

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms.

Efficacy of Weight Reduction on Pediatric Nonalcoholic Fatty Liver Disease: Opportunities to Improve Treatment Outcomes Through Pharmacotherapy.

Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low.

Critical need for pharmacologic treatment options in NAFLD: A pediatric perspective.

Nonalcoholic fatty liver disease (NAFLD) affects up to 70% of children with obesity and has become the number one etiology for liver transplant in the United States. Early, effective intervention is critical to prevent disease progression into adulthood. Yet, it is seldom achieved through lifestyle modification alone.

Functional Consequences of Pravastatin Isomerization on OATP1B1-Mediated Transport.

Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3'-iso-pravastatin acid (3PVA) under acidic pH conditions. Previous studies reported interindividual differences in circulating concentrations of PVA and 3PVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport.

Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia.

This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 13; 521CC, n = 2) and wild type controls (521TT, n = 13) completed a single oral dose pharmacokinetic study.

Results of the FUEL Trial.

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking.

A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents.

Purpose: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status.

Methods: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents.

Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia.

This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study.

Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics.

This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study.

A Rare Case of Vascular Ring and Coarctation of the Aorta in Association with CHARGE Syndrome.

A male neonate presented with CHARGE syndrome, a multiorgan genetic disorder involving the Coloboma of the eyes, congenital Heart defects, nasal choanal Atresia, growth and development Retardation, Genitourinary disorders, and Ear anomalies and deafness. Moreover, he had a rare case of vascular ring-consisting of a right aortic arch with retroesophageal brachiocephalic artery-combined with coarctation of the mid-aortic arch. He underwent both vascular ring and aortic arch repair at our institution.

Quantification of pravastatin acid, lactone and isomers in human plasma by UHPLC-MS/MS and its application to a pediatric pharmacokinetic study.

An ultra high pressure liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for the simultaneous quantitation of pravastatin and major metabolites, 3'α-hydroxy-pravastatin, pravalactone and 3'α-hydroxy-pravalactone, in human plasma has been developed and validated. Aliquots of (100μL) plasma in EDTA were diluted in pH 4.5 (0.

Genomics and Precision Medicine to Direct Statin Use in the Young.

The delivery of precision medicine to pediatric cardiology remains complex with a number of challenges ahead. With recent advances in whole genome sequencing, rapid acquisition of a patient's genomic data is possible. However, the challenge remains how we best implement this new data into clinical practice.