Pharmacokinetics of Pravastatin and Simvastatin in Pediatric Dyslipidemia Patients: Clinical Impact of Genetic Variation in Statin Disposition

The ultimate goal of this proposed investigation is to establish the role of genetic variation and development 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.

Research Design and Methods

1. Trial Design 1.1. Investigational Agents Pravastatin 20 mg tablet (ages 8-13 years), 40 mg tablet (>14 years) Simvastatin 10 mg tablet (ages 8-17), 20mg (>17 years) Commercial supplies of pravastatin and simvastatin that are FDA approved for use in pediatric dyslipidemia will be used. Pravastatin and simvastatin from the same source and lot will be used for all subjects. The doses designated above are chosen according to previous adult and pediatric data 26, 28-32, 41 and are consistent with current labeling for pravastatin and simvastatin. Although fixed doses within a pre-specified age range will be used, dose data will be analyzed corrected for weight (mg/kg) based on the patient's weight at time of dosing.

1.2. Risk/Benefits All subjects with a LDL >130mg/dl (95% percentile) will be eligible for this study, consistent with current clinical criteria for statin therapy. The risks associated with participation in this single-dose pharmacokinetic study are expected to be minimal given the known adverse event profile for the study articles and also, the limited exposure. The most common mild adverse effects of statins are headache, myalgia, and gastrointestinal symptoms (abdominal pain, dyspepsia, diarrhea, constipation). However, in children these adverse effects occur with the same frequency as placebo 14, 15, 18. Rare adverse effects include elevation of hepatic transaminases and myopathy, but these are generally observed with chronic treatment. Furthermore, no cases of hepatic failure with statins have been reported to date 52. There is also a small risk associated with placement of the intravenous (IV) catheter that will be used to draw serial blood samples for pharmacokinetic analysis and screening/safety labs. Finally, there is the risk of loss of confidentiality for the participating subjects. Methods to protect PHI and data handling are specifically outlined in the CMH CPR protocol Sections 4 & 5 (CMH IRB# 12040220). All of the above risks associated with this non-therapeutic clinical trial are minimal.

There is no direct benefit to participating subjects, although there may be benefit for children in the future as it is expected that the information to be gained from the study can be generalized to the larger population of pediatric patients who may require statin treatment. The purpose of the study is to determine how genetic variation impacts pravastatin and simvastatin plasma concentrations following recommended doses of the drug in a patient population that has not previously been studied. Thus, with this knowledge, future protocols could subsequently be developed to effectively "personalize" dosing for pediatric subjects with the aforementioned SNPs who are taking pravastatin or simvastatin, thereby improving efficacy and safety for the individual patient.