Pharmacokinetics of Rosuvastatin and Atorvastatin in Pediatric Dyslipidemia Patients

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.

Inclusion Criteria:

1. Children 8-21 years of age

2. LDL cholesterol >130mg/dl (>95% percentile)

3. Successfully genotyped for SLCO1B1

4. Willing to sign the assent/permission/consent form

Exclusion Criteria:

1. Underlying structural heart disease including congenital heart disease or acquired
heart disease.

2. History or laboratory evidence of an underlying intestinal, metabolic, autoimmune, or
renal disease that could alter the disposition of rosuvastatin or atorvastatin.

3. Underlying pathology of the gastrointestinal tract or recent surgery which would be
expected to alter the rate and/or extent of drug absorption

4. Evidence of previous hypersensitivity to statin medications

5. Unwillingness or inability to have screening labs drawn

6. Refusal to participate in the study

7. Unwillingness or inability to participate in an overnight fast

8. Subjects taking drugs with interactions with statins (CYP3A4 inducers/inhibitors,
OATP1B1 inducers/inhibitors) (Appendix 1)

9. Inability to swallow a tablet drug

10. For females, a positive urine beta-human chorionic gonadotropin pregnancy test result

11. Evidence of hepatic abnormality as determined by values > 3 times the age-specific
upper limit of normal for AST, ALT, total and conjugated bilirubin, serum albumin,
Alkaline Phosphatase, and GGT.

12. Abnormal red blood cell morphology and/or a hemoglobin less than 9 gm/dl

13. Diarrhea in the last 24 hours