dosing compared with the traditional fixed-dose approach.53 Despite improvement with a pharmacogenetic-based algorithm compared to traditional fixed dosing, these pharmacogenetic-based algorithms still resulted in more than 50% of the patients with subtherapeutic and/or supratherapeutic predictions Overall, there have been substantial gains in the development and implementation of combined clinical and pharmacogenetic-based warfarin dosing algorithms in pediatrics, but they still require further refinement Clopidogrel, an irreversible purinergic P2RY12 receptor inhibitor preventing ADP-induced platelet aggregation, is administered as a thienopyridine prodrug that requires CYP-mediated bioactivation to form its active metabolite.54,55 The majority of the existing pharmacogenetic data related to the influence of CYP2C19 allelic variation on bleeding and other adverse events (e.g., stent thrombosis) resides in adults with acute coronary syndrome undergoing percutaneous coronary interventions (PCIs) One or more loss-of-function allele(s) (e.g., CYP2C19*2, CYP2C19*3) reduce activation of clopidogrel, leading to a significantly lower systemic exposure (e.g., AUC) of active metabolites compared with those with the reference genotype (CYP2C19*1/*1),56 leading to a decreased pharmacodynamics effect (e.g., lower inhibition of platelet aggregation) and increased risk of thrombotic events.56–58 Utilization of clopidogrel in children with congenital or acquired heart disease, comparatively, has been limited Among infants with a systemic-to-pulmonary artery shunt, clopidogrel, as dual therapy with aspirin, failed to improve the rate of shunt thrombosis compared with aspirin as monotherapy in the Clopidogrel to Lower Arterial Thrombotic Risk in Neonates and Infants Trial (CLARINET) trial.59 From a developmental pharmacology perspective, the question arises whether these younger infants, due to CYP2C19 immaturity, had insufficient CYP2C19 expression to even activate clopidogrel and thus prevent platelet aggregation Of note, there is significant variability in CYP2C19 expression among infants and children in the aforementioned data from Koukouritaki et al.22 secondary to ontogeny but additionally due to CYP2C19 genetic variation Absent from the CLARINET trial was the individual CYP2C19 genotype to ascertain whether those in the clopidogrel arm had loss-of-function CYP2C19 alleles CPIC guidelines recommend considering an alternative agent in poor (e.g., CYP2C19*2/*2, *2/*3, *3/*3) or intermediate (e.g., CYP2C19 *1/*2, *1/*3) metabolizers.27 Obviously there are few data regarding the genotypephenotype relationship of CYP2C19 in the developing child to include formally in the CPIC guidelines, but secondary analyses of existing pharmacodynamics data sets could provide preliminary data to justify and inform prospective trials involving the pharmacogenetic impact on clopidogrel or other CYP2C19 substrates during childhood Statins 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are now the mainstay of pharmacologic treatment for adult and pediatric hypercholesterolemia due to their demonstrated efficacy in the primary and secondary prevention of coronary artery disease.60–64 To date, pediatric statin trials have focused on short-term lipid lowering and safety outcomes.65–74 Three double-blind, randomized, placebo-controlled trials of pravastatin and simvastatin in children have demonstrated an approximate 25% to 35% and 40% reduction in low-density lipoprotein (LDL), respectively, validating their efficacy in this age group.67,68,70 Of concern, daily administration of relatively high doses for greater than 36 weeks was accompanied by a considerable (~fourfold) interindividual variability in drug response as indicated by decreases in LDL.67,68,70 With few exceptions, exposure to statins has conferred no added short-term safety risk compared with placebo However, in the existing pediatric trials, the duration of therapy ranged from 1 month to 2 years; thus there are few data describing the safety of chronic exposure to statins initiated during childhood With this large degree of variability in response and unknown effects of chronic statin administration on maturing gonadal and brain tissues, determining the lowest dose that achieves maximal response with minimal risk of toxicity (dose optimization) is of great importance in the developing child One potential source of interindividual variability in statin response is variability in circulating plasma statin concentrations, referred to as the systemic exposure, due to genetic variation in the drug transporters responsible for the translocation of statins across membranes In particular, the c.521T>C singlenucleotide variant (SNV; rs4149056) in the SLCO1B1 gene encoding the hepatic drug transporter OATP1B1 affects the localization of the transporter on the basolateral membrane of the human hepatocyte (Fig 79.4).75 The functional consequence of this SNV is decreased hepatocyte uptake75 and increased systemic statin exposure.76,77 Investigations by Niemi et al.76 and Pasanen et al.77 have demonstrated that the SLCO1B1 c.521T>C variation is associated with a significant increase in pravastatin and simvastatin acid (SVA) AUC compared with subjects homozygous for the fully functional reference allele (c.521TT genotype) Clinically significant adverse events (i.e., myalgias) are reported to be greatest in the presence of c.521C alleles78,79 because of increased systemic exposure Although some studies have also demonstrated an association between lipid lowering and the SLCO1B1 c.521T>C allelic variant,80,81 an equal number of publications have found no effect of SLCO1B1 c.521T>C on LDL lowering.82,83 CPIC dosing guidelines for simvastatin based on SLCO1B1 genotype recommend that patients with intermediate to low OATP1B1 function have a lower dose of simvastatin or an alternative statin (e.g., pravastatin, rosuvastatin) prescribed.84 Currently there are no recommendations with regards to statin dosing according to SLCO1B1 genotype in children However, recent data from a pharmacogenomics-driven pharmacokinetic analysis involving pravastatin and simvastatin demonstrate that the magnitude of the SLCO1B1 effect in children is twofold greater compared with that observed in adults.85,86 FIG 79.4 Statin disposition pathway in the hepatocyte Hepatic uptake of statins occurs via passive diffusion or a transport-mediated process based on the lipid/water partition properties of the drugs Within the hepatocyte, statins block HMG-CoA reductase (HMGCR), the rate-limiting step of cholesterol biosynthesis Hepatic clearance into the bile (green) occurs primarily through efflux transporters located on the biliary canaliculus BCRP, Breast cancer resistance protein; BSEP, bile salt export pump; HMG, 3-Hydroxy-3-methyl-glutaryl; LDL, low-density lipoprotein; MDP, multidrug resistance protein; NTCP, sodium/taurocholate cotransporting polypeptide ... (statins) are now the mainstay of pharmacologic treatment for adult and pediatric hypercholesterolemia due to their demonstrated efficacy in the primary and secondary prevention of coronary artery disease.60–64 To date, pediatric statin trials have focused on short-term lipid lowering and safety outcomes.65–74 Three... in LDL.67,68,70 With few exceptions, exposure to statins has conferred no added short-term safety risk compared with placebo However, in the existing pediatric trials, the duration of therapy ranged from 1 month to 2 years; thus there are few data describing the safety of chronic exposure to statins initiated during