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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. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration-time curve from 0-24 hours (AUC0-24 ) was 1.4-fold and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Interindividual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~ 1.5-fold to 2-fold difference in mean RVA exposure observed among SLCO1B1 genotype groups, suggesting that other factors also contribute to interindividual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC0-24 . However, of the statins investigated to date in the pediatric population, RVA has the lowest magnitude of variability in systemic exposure.

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. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.

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. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.

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 C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites. Conclusion The model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents. Electronic supplementary material The online version of this article (10.1007/s00228-019-02697-y) contains supplementary material, which is available to authorized users.

Introduction: Complex single ventricle congenital heart disease (CHD) patients are subject to multiple stressors early in life that affect somatic growth. Pre-Fontan growth patterns are well-described, but post-Fontan growth has not been extensively studied in the current era. We sought to describe post-Fontan growth patterns by creating sex-specific body mass index (BMI)-for-age curves. Hypothesis: There is no difference in the growth of post-Fontan pediatric patients when compared to published normative data. Methods: A single-center, preexisting database was retrospectively queried for all patients who underwent Fontan procedure between 2006 and 2018. Patients with a genetic syndrome, a primary endocrine disorder, or significant prematurity were excluded. BMI-for-age curves were created for both male and female patients using anthropometric data extracted from the electronic medical record. Curves were then visually compared with Centers for Disease Control and Prevention (CDC) growth charts. Results: Of 227 patients who underwent primary Fontan operation, 37 were excluded. Of the remaining 190 patients, 59% were male. All had an extracardiac conduit, half had right-ventricular dominant CHD, and 15% had a Fontan fenestration. Median age and weight at surgery were 3.9 years and 15 kilograms, respectively. BMI curves were similar in appearance to CDC BMI-for-age growth charts, with adiposity rebound at age 6. BMI increased more rapidly in teen boys compared with girls, and a total of five patients (2.6%) had BMI values greater than 25 kg/m 2 at 16 years of age. Conclusion: Post-Fontan patients at our institution demonstrate BMI-for-age patterns similar to those of the general population during childhood and early adolescence, with adiposity rebound occurring at a typical age. Though excess weight gain does not completely spare patients with single ventricle CHD, overweight status appears to be less common than in the general pediatric population.

Background: The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity and ventricular performance following six months of treatment with udenafil (87.5 mg twice daily). In this analysis we evaluated whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. Methods: The effect of udenafil on exercise was evaluated within subgroups defined by gender, race, ventricular morphology, and baseline peak oxygen consumption (VO 2 ). Linear regression modeling evaluated for differential response to udenafil (interaction of subgroup with treatment arm). Individual subgroups were excluded if the number of participants was Results: Subgroup analyses demonstrated qualitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in all subgroups (Table). There was not a differential response to udenafil based on gender, race, ventricular morphology, or baseline peak VO 2 , although participants in the lowest tertile of baseline peak VO 2 and those with single left ventricles trended toward larger improvements. Conclusion: The relatively uniform improvement among subgroups in response to treatment with udenafil is consistent with the findings from the primary analysis of the FUEL trial. While the absence of a statistically significant differential effect between subgroups suggests that the effect of udenafil may not be gender, race, or morphology specific, and may not vary based on baseline exercise performance, the possibility of a larger improvements in those with poor baseline peak VO 2 and those with single left ventricle warrants further investigation.

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. Predicting drug disposition and response of the individual patient requires a thorough knowledge of the entire dose-exposure-response relationship of each individual drug and knowledge of the factors that make each individual unique. This goal of precision medicine is even more complex in the developing child where drug disposition and response pathways may still be maturing. Herein, we will illustrate the challenges and pitfalls that may occur when trying to deliver pediatric precision medicine using the statins as a prototype.

In the very young child (less than eight years of age), transient loss of consciousness represents a diagnostic and management dilemma for clinicians. While most commonly benign, syncope may be due to cardiac dysfunction which can be life-threatening. It can be secondary to an underlying ion channelopathy, cardiac inflammation, cardiac ischemia, congenital heart disease, cardiomyopathy, or pulmonary hypertension. Patients with genetic disorders require careful evaluation for a cardiac cause of syncope. Among the noncardiac causes, vasovagal syncope is the most common etiology. Breath-holding spells are commonly seen in this age group. Other causes of transient loss of consciousness include seizures, neurovascular pathology, head trauma, psychogenic pseudosyncope, and factitious disorder imposed on another and other forms of child abuse. A detailed social, present, past medical, and family medical history is important when evaluating loss of consciousness in the very young. Concerning characteristics of syncope include lack of prodromal symptoms, no preceding postural changes or occurring in a supine position, after exertion or a loud noise. A family history of sudden unexplained death, ion channelopathy, cardiomyopathy, or congenital deafness merits further evaluation. Due to inherent challenges in diagnosis at this age, often there is a lower threshold for referral to a specialist.

Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3′α-iso-pravastatin acid (3αPVA) under acidic pH conditions. Previous studies reported interindividual differences in circulating concentrations of PVA and 3αPVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3αPVA inhibition of OATP1B1-mediated PVA uptake into human embryonic kidney 293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5, and *15). 3αPVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC(50)/K(i) values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3αPVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (V(max) values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3αPVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3αPVA was higher (lower K(m) value) than for PVA. These data confirm that PVA conversion to 3αPVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. SIGNIFICANCE STATEMENT: 3′α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types; however, the IC(50) values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3′α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant-expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin interindividual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.

Obesity rates continue to rise in children, and little guidance exists regarding the need for adjustment away from total body weight-based doses for those prescribing drugs to this population of children. A majority of drugs prescribed to children with obesity result in either sub-therapeutic or supra-therapeutic concentrations, placing these children at risk for treatment failure and drug toxicities. In this review, we highlight available obesity-specific pharmacokinetic and dosing information for the most frequently prescribed drugs to children in the inpatient and outpatient clinical settings. We also comment on available dosing recommendations for drugs prescribed to treat common pediatric obesity-related comorbidities. This review highlights that there is no safe or proven 'rule of thumb,' for dosing drugs for children with obesity, and a striking lack of pharmacokinetic data to support the creation of dosing guidelines for children with obesity for the most commonly prescribed drugs. It is important that those prescribing for children with obesity are aware of these gaps in knowledge and of potential drug treatment failure or adverse events related to drug toxicity as a result of these knowledge gaps. Until more data are available, we recommend close monitoring of drug response and adverse events in children with obesity receiving commonly prescribed drugs.

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. To our knowledge, this is the 4th documented case of this exceedingly rare type of aortic arch anomaly combined with aortic arch obstruction. Moreover, it is the first confirmed case of these combined disorders occurring in CHARGE syndrome. This report describes a truly rare case and reveals the limitations of echocardiography in detecting complex aortic arch anomalies while illustrating the benefits of advanced imaging prior to surgical intervention.

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. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.

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 (0.1M buffer) to stabilize the analytes and subjected to hydrophilic lipophilic balance (HLB) solid phase extraction on 96 well μelution plates. Extracted samples were evaporated to dryness and reconstituted in pH 4.5 buffer. Chromatographic separation was performed on a Cortecs™ C18 column (2.1×100mm, 1.8μm), using gradient elution with a blend of acetonitrile and 10mM methylammonium acetate buffer (pH 4.5) at a flow rate of 0.4mL/min. Mass spectrometric detection was performed using multiple reaction monitoring (MRM) switching between positive/negative electrospay ionization (ESI). Pravastatin, 3'α-hydroxy-pravastatin, and internal standards [(2)H3]-pravastatin, and [(2)H3]-3'α-hydroxy-pravastatin were monitored in negative ESI mode at ion transitions m/z 423.2→321.1 and 426.2→321.1, respectively. Positive ESI mode was used for the detection of pravalactone, 3'α-hydroxy-pravalactone, and internal standards [(2)H3]-pravalactone, and [(2)H3]-3'α-hydroxy-pravalactone at ion transitions m/z 438.2→183.1 and 441.2→269.1 respectively. The method was linear for all analytes in the concentration range 0.5-200nM with intra- and inter-day precisions (as relative standard deviation) of ≤5.2% and accuracy (as relative error) of ≤8.0% at all quality control levels. The method was successfully applied to the investigation of pharmacokinetic properties of pravastatin and its metabolites in children after an oral dose of 20-40mg.

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. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (Cmax , 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on response rather than only the dose-exposure relationship. The amount of drug target receptors and the relative affinity for binding at that target site may require different levels of systemic exposure to achieve a desired response. Concentration-controlled studies can identify the needed exposure for a response at the drug target, the level of expression of the target site in an individual patient, and the tools required to individualize response. Although pediatrics represents a large spectrum of growth and development, developing tools to improve drug delivery for each individual patient across the spectrum of the ages treated by clinicians remains valuable.

Cerebral embolization during pediatric cardiac surgery may be an underappreciated source of subsequent neurodevelopmental impairment. Transcranial Doppler ultrasound is a neuromonitoring tool that can provide intraoperative surveillance for cerebral embolization. We hypothesized that increased cerebral embolic signals detected during infant cardiac surgery would be associated with worse neurodevelopmental outcomes at follow-up. A study group of 24 children who underwent infant cardiac surgery with transcranial Doppler detection of cerebral embolic signals returned at intermediate follow-up for standardized neurodevelopmental assessment. The children were evaluated using two neurocognitive tests and the parents completed two questionnaires regarding observed behavior. Statistical analysis assessed for correlation between the number of cerebral embolic signals at surgery and the results of the neurodevelopmental assessment. Of the 67 test parameters analyzed, five showed a significant association with the number of embolic signals, yet, all in the contrary direction of the clinical hypothesis, likely representing a Type I error. Thus, in this small cohort of patients, the number of cerebral embolic signals detected during infant cardiac surgery was not shown to be associated with worse neurodevelopmental outcomes at intermediate follow-up. A larger study is probably necessary to ascertain the potential influence of cerebral embolic signals on eventual neurologic outcomes in children. The clinical relevance of cerebral embolic signals during pediatric cardiac surgery remains undetermined and deserves further investigation.

Cardiac myxoma is the most common cardiac tumor in patients of all ages; the majority are encountered as single left atrial tumors. Left ventricular myxomas are exceedingly rare, having been recorded in a small number of case reports involving children worldwide. We report a case of a left ventricular myxoma with left ventricular outflow tract obstruction in a previously healthy, asymptomatic adolescent black male. Transthoracic echocardiograms revealed a single, large (2.5 × 5-cm), lobulated, mobile mass within the left ventricular cavity that oscillated into the outflow tract, thereby causing moderate obstruction during systole. Advanced images delineated the location and tissue composition of the mass, characterizing it as a myxoma. Complete surgical excision of the mass was accomplished via aortotomy. Gross examination and histology confirmed the diagnosis of myxoma.

The dose-exposure-response relationship for drugs may differ in pediatric patients compared with adults. Many clinical studies have established drug dose-exposure relationships across the pediatric age spectrum; however, genetic variation was seldom included. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies.

A 16-year-old Hispanic girl with arrhythmogenic right-ventricle dysplasia (ARVD) presented with angina pectoris and troponin increase on three occasions. There was a family history of sudden cardiac death in a cousin. Her mother was diagnosed with ARVD. The patient herself had a history of nonsustained ventricular tachycardia but did not meet diagnostic criteria for ARVD. Cardiac workup, including serial transthoracic echocardiograms and a coronary angiogram, showed a structurally normal heart without coronary artery stenosis. Results of cardiac magnetic resonance imaging were questionable, but endomyocardial biopsy did not show evidence of viral myocarditis by polymerase chain reaction. Genetic testing confirmed ARVD.

OBJECTIVES/SPECIFIC AIMS: In the present study, we examined the functional consequences of 3α-PVA on OATP1B1-mediated PVA transport. To elucidate this, we determined the effect of SLCO1B1 genotype on PVA transport and the role of 3αPVA as a competitive inhibitor of OATP1B1, which could serve as another covariate that disrupts the systemic and hepatic exposure of pravastatin in children and adults. METHODS/STUDY POPULATION: Site directed mutagenesis was performed to generate SLCO1B1 genotypes of interest (*1a, *1b, *5, *15). Human embryonic kidney (HEK293) cells were grown and plated at 200 000 cells per well in 24-well plates. Twenty-four hours later the cells were transfected with the aforementioned plasmids. Forty-eight hours later cell-based transport was performed with radiolabelled [3H]-pravastatin sodium salt. Non-radioactive pravastatin sodium salt and 3’α-iso-pravastatin sodium salt was used for PVA transport and 3αPVA studies, respectively. Cells were washed 3 times with warm uptake buffer, incubated for 1 minute with uptake solutions containing PVA and 3αPVA at varying concentrations. Transport was terminated by four 1-ml washes with ice-cold uptake buffer. Cells were lysed with 300 µl 1% Triton X-100 in PBS at room temperature for 30 minutes prior to analysis. Radioactivity was measured in a MicroBeta2 liquid scintillation counter. The remaining cell lysates were transferred to 96-well plates to determine total protein concentration using the bicinchonic acid protein assay. All transport measurements were corrected by the total protein concentration. All experiments were performed 3 to 4 times independently with 2-3 determinations. Data were analyzed for significant differences amongst genotype groups using ANOVA followed by Tukey’s multiple comparisons test. IC50 and kinetic parameters were calculated using non-linear regression analysis. RESULTS/ANTICIPATED RESULTS: Pravastatin transport in SLCO1B1 variants (*5, *15) was significantly decreased compared to the reference genotype *1a and *1b (Km [µM]: *1a 18.2 ± 0.9; *1b 17.9 ± 3.3; *5 34.2 ± 9.7; *15 34.1 ± 6.1; p≤0.05; Vmax [pmol/mg/min]: *1a 104.9 ± 13.1; *1b 93.7 ± 16.7; *5 44.8 ± 15.9; *15 62.3 ± 22.5; p≤0.05). *1a and *1b were not significantly different with respect to pravastatin transport. Intrinsic clearance was diminished nearly 4 to 5-fold in SLCO1B1 variants compared to reference genotypes (Vmax/Km [µl/min/mg]: *1a 5.8 ± 0.8; *1b 5.7 ± 1.9; *5 1.3 ± 0.2; *15 1.8 ± 0.3; p≤0.01). Pravastatin transport was inhibited by 3αPVA for all genotypes. However, there was more pronounced inhibition in the SLCO1B1 variant genotypes compared to reference genotypes (IC50 [µM]: *1a 15.9 ± 1.9; *1b 18.6 ± 5.7; *5 3.9 ± 2.0; *15 4.4 ± 0.8; p≤0.01; Ki: *1a 15.0 ± 1.8; *1b 17.5 ± 5.4; *5 3.8 ± 2.9; *15 4.3 ± 0.8; p≤0.01). DISCUSSION/SIGNIFICANCE OF IMPACT: In vitro PVA transport is altered according to SLCO1B1 genotype, consistent with previous in vitro and human experience. Our data suggest that the significantly different maximal transport velocity (Vmax) in variant versus non-variant genotypes is consistent with decreased membrane expression of OATP1B1 with the variant c.521T>C allele. However, in contrast to data involving typical model substrates (e.g. estrone-3-sulfate), the PVA binding affinity (Km) was significantly different between variant and non-variant genotypes, consistent with altered binding of the substrate to OATP1B1. Collectively, we conclude that decreased OATP1B1 expression and function in variant genotypes influence altered transport for PVA. Finally, the functional consequences of 3αPVA formation on PVA transport was confirmed in our study. Mechanistically, we confirmed our observation in humans that 3αPVA inhibits OATP1B1 transport. However, this effect is more pronounced in variant genotypes as shown by lower IC50 values compared to the reference genotypes. This highlights another source of variation that must be taken into consideration when trying to optimize the pravastatin dose-exposure relationship in humans.

Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs.