Dose-Exposure-Response Relationship Pediatric pharmacotherapy, similar to adult pharmacotherapy, is dependent on a clear understanding of the dose-exposure-response relationship of the administered drug to predict a response for a given dose Providers must recognize that many drug (e.g., formulation, protein binding affinity coefficient, physicochemical properties) and patient factors (e.g., age, Tanner staging, cardiac physiology, altered drug metabolism or transport) contribute to the systemic exposure (e.g., dose-exposure relationship) of a drug for the individual child and thereby influences drug response For example, poor responders to a particular drug may not have genetic variation of the drug target affecting response but alternatively have insufficient exposure at the drug target to generate an adequate response Fig 79.2 illustrates the complexity involved in precision-guided therapy, outlining each level of the drug disposition pathway, absorption through elimination, that must be considered as a potential source for variable drug exposure (e.g., dose-exposure relationship) FIG 79.2 Dose-exposure-response relationship Following drug administration by the oral route, absorption occurs passively or through a transport-mediated process in the enterocyte Drug metabolizing enzymes (DMEs) at the level of the enterocyte can contribute for selective substrates to the presystemic clearance of orally administered drugs Following absorption, drugs entering the portal venous system can undergo a firstpass effect at the level of the hepatocyte, either passively or through transport-mediated uptake DMEs can activate or deactivate selective drugs and conjugate them for elimination Drugs entering systemic circulation can be cleared by renal tubule cells Alternatively, drugs administered intravenously enter systemic circulation directly Collectively, one must factor all the steps of drug disposition (e.g., dose-exposure relationship) first prior to implementing pharmacogenomics testing at the response level Even when the dose-exposure relationship has been optimized, variable drug response can be a product of two mechanisms: (1) abnormal drug-target interaction (e.g., drug target genetic variation) or (2) abnormal drug-target signaling following a normal drug-target interaction As alluded to earlier, before development and genetic variation at the drug targets and associated signaling pathways (e.g., response pathways) are considered in clinical practice for precision-guided therapy, it is crucial to initially determine if genetic variation contributing to altered systemic exposure is the source of variable response, meaning that the perceived response is not secondary to poor or excessive drug exposure at the drug target A recent review of developmental pharmacology described the known development aspects of drug disposition that should be considered for pediatrics.5 In pediatric pharmacotherapy, extrapolation of adult experiences is complicated by age-associated differences in the pharmacokinetics of several pharmacologic agents used clinically in children.7 Therefore development (e.g., ontogeny of drug metabolizing enzymes or transporters) is another consideration that must be added when characterizing the dose-exposure relationship in a child Until we understand and fully characterize the pediatric drug disposition pathways, it will not be feasible to control the exposure at the drug target following a given dose in a manner that will improve clinical trial outcomes Genotype-stratified pharmacokinetic studies performed separately in a pediatric cohort, described in the section Practical Applications: Statins, allow for full characterization of the anticipated extremes of the dose-exposure relationship Subsequently, these initial data assist in the development of pharmacogenomic investigations utilizing individualized dosing to achieve a target exposure and reduce interindividual variability.4 Collectively, pharmacogenomics can be utilized to enhance pediatric dosing guidelines and provide precision-guided care In the absence of more comprehensive pediatric data, however, a systematic approach has been developed to gather more information about certain drugs and identify knowledge gaps to more accurately inform prospective pediatric trials and clinical decision making.3,8 The fundamental questions outlined in these referenced manuscripts are as follows (1) What gene products are quantitatively important in the disposition (absorption, distribution, metabolism, and excretion) of the drug? (2) What known allelic variants in the genes of interest are associated with functional consequence in vivo? (3) What is the developmental profile (ontogeny) of the key pathways involved in the drug's disposition? ... A recent review of developmental pharmacology described the known development aspects of drug disposition that should be considered for pediatrics.5 In pediatric pharmacotherapy, extrapolation of adult experiences is complicated by age-associated differences in the pharmacokinetics of several... target exposure and reduce interindividual variability.4 Collectively, pharmacogenomics can be utilized to enhance pediatric dosing guidelines and provide precision-guided care In the absence of more comprehensive pediatric data, however, a systematic approach has been developed to gather more information about certain drugs and... following a given dose in a manner that will improve clinical trial outcomes Genotype-stratified pharmacokinetic studies performed separately in a pediatric cohort, described in the section Practical Applications: Statins, allow for full characterization of the anticipated extremes of the dose-exposure