Anticipating an increased use of statins in children and adolescents, it is imperative that
we understand the genetic and developmental characteristics affecting the pharmacokinetics
and pharmacodynamics of statins in childhood and adolescence. Simply extrapolating pediatric
dosing guidelines from adult dose-exposure-response relationships fails to recognize the
potential impact of growth and development in pediatric patients, which may have important
clinical implications for drug efficacy or toxicity. Current evidence indicates that genetic
variation in the SLCO1B1 transporter is important for statin disposition and toxicity in
adults. The ontogeny of SLCO1B1 during human growth and development has not been well
characterized, and limited pediatric data indicate that the genotype-phenotype relationship
in children is the opposite of that observed in adults. Therefore, investigating the relative
roles of SLCO1B1 ontogeny and genetic variation in statin disposition and response is key to
determining the age at which the statin dose-exposure-response relationship mimics adults,
and has important implications for other medications transported by the SLCO1B1 protein.
As the first step in this process, our specific aims for the current investigation are 1) to
determine the effect of genetic variation of SLCO1B1 on the pharmacokinetics of pravastatin
and simvastatin by comparing Cmax, AUC and elimination between children and adolescents with
2 functional SLCO1B1 alleles and those with one or more variant alleles, and 2) to determine
if the magnitude of the genetic effect on pravastatin pharmacokinetics (defined as Cmax, AUC
and elimination) is equivalent to the effect on simvastatin pharmacokinetics. As a secondary
aim, Cmax and AUC of pravastatin and simvastatin will be compared between children and
adolescents for each genotype group. These results will be utilized to determine the sample
size necessary to adequately power future studies characterizing the role of ontogeny on
statin disposition.
The ultimate goal of this proposed investigation is to establish the role of genetic
variation in key transporters on the dose-exposure relationship of two commonly used statin
drugs in children. This study is the first step in a series of investigations aimed at
determining the mechanisms behind variations in physiologic response, clinical efficacy and
significant adverse effect risk that surround the statin drugs in children and adolescents.