Pharmacokinetics of Rosuvastatin and Atorvastatin in Pediatric Dyslipidemia Patients
Condition: Dyslipidemia
MeSH terms: Dyslipidemias
Study type: Interventional
Phase: Phase 1

Summary: 
      This will be a single center, open label, randomized, cross-over study in patients with
      dyslipidemia comparing the pharmacokinetics of rosuvastatin and atorvastatin in patients with
      greater than or equal to one variant allele in the SLCO1B1 gene (-11187 and/or c.521) to
      patients with the wild-type/wild-type genotype.

      The studies goal 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 to determining the
      mechanisms behind variations in physiologic response, clinical efficacy and significant
      adverse effect risk that surround the statin drugs in children and adolescents.
    

Detailed description: 
      Trial Design

      Investigational Agents:

      Rosuvastatin 10mg tablet (ages 8-21 years); oral dosing Atorvastatin 10mg tablet (ages 8-21
      years); oral dosing Commercial supplies of rosuvastatin and atorvastatin that are FDA
      approved for use in pediatric dyslipidemia will be used. Rosuvastatin and atorvastatin from
      the same source and lot will be used for all subjects.

      Dose Rationale:

      The doses designated above are chosen according to previous pediatric data13,14, and are
      consistent with current labeling for rosuvastatin and atorvastatin in children greater than
      10 years of age. The rosuvastatin and atorvastatin doses will be off label for participants
      8-10 years of age, but consistent with current practice. Data from this study are not
      intended to be used to change the drug labeling, and thus a new IND is not required. 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.

      Risk/Benefits:

      All eligible subjects with a LDL >130mg/dl (95% percentile) meet 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 placebo7,10,25. 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 date10. 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
      rosuvastatin and atorvastatin 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 rosuvastatin and atorvastatin,
      thereby improving efficacy and safety for the individual patient.

      Study Design/Type:

      This will be a single center, open-label, randomized, crossover pilot study in patients with
      dyslipidemia comparing the pharmacokinetics of rosuvastatin and atorvastatin in patients with
      greater than or equal to one variant allele in the SLCO1B1 gene (-11187 and/or c.521) to
      patients with the wild-type/wild-type genotype. The results of genetic testing will not be
      disclosed to the subjects.

      Population Sample:

      The CMH Cardiology Pharmacogenomics Repository (CPR) (CMH IRB# 12040220) database will be
      accessed to determine subjects meeting inclusion/exclusion criteria. The study population
      from the aforementioned IRB proposal has already agreed to be contacted for future studies.
      Once the target population and an equal set of age, sex-, race- and Tanner Stage-matched
      controls are identified, the patients will be invited to participate.

      Subject Recruitment:

      Once a target population and an equal set of age-, sex- and Tanner Stage-matched controls are
      identified from the CPR, prospective participants will be informed about the study. Initial
      contact will occur by way of a prepared telephone script (Appendix 2&3). Those that agree to
      participate will be scheduled for a visit to the Pediatric Clinical Research Unit (PCRU) for
      a screening visit. At this visit, the study will be explained to the patient/patient's
      family, permission/assent/consent (Appendix 4&5) will be obtained, a physical examination
      (including Tanner staging), and screening laboratory testing will be performed. Participants
      for whom permission/assent/consent has been obtained and inclusion criteria are met, will be
      scheduled to come back to the PCRU for the first study drug day. If the participant is
      currently on a statin, they will not be scheduled to come back for at least 6 days for Study
      Drug Day #1 (washout period). This visit will need to be conducted following a minimum of 6
      days and up to 14 days for these participants. If the participant is not currently on a
      statin then they can be scheduled anytime after their screening visit is complete. The visit
      will consist of a physical examination, lab tests, placement of an indwelling venous cannula
      for serial blood draws as outlined below and administration of a single oral dose of
      rosuvastatin or atorvastatin. The total amount of blood drawn (screening labs and PK samples)
      for the trial will be 60.6 ml, which is well within the guidelines placed at CMH ORI for
      children > 25 kg. This study will require an overnight stay in the PCRU in order to obtain
      all necessary plasma levels. Following a minimum of 6 days and up to 14 days after the study
      day #1 (washout period), the participating subject will be brought back to the PCRU for
      another single dose pharmacokinetic study involving the second drug with the same procedure
      and sampling scheme as conducted in study day #1.
    

Intervention name(s): Rosuvastatin; Atorvastatin
Intervention type(s): Drug; Drug
Intervention description(s): Rosuvastatin 10mg tablet (ages 8-21 years); 1 time dose given per oral at the start of the study day.; Atorvastatin 10mg tablet (ages 8-21 years); 1 time dose given per oral at the start of the study day.
Other intervention name(s): Crestor; Lipitor
Intervention MeSH terms: Atorvastatin; Rosuvastatin Calcium
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment