Pharmacokinetics of Rosuvastatin and Atorvastatin in Pediatric Dyslipidemia Patients: Clinical Impact of Genetic Variation in Statin Disposition
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Evaluate effect of genotype (SLCO1B1) on AUC atorvastatin
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 8 Years to 21 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Children 8-21 years of age
- •LDL cholesterol >130mg/dl (>95% percentile)
- •Successfully genotyped for SLCO1B1
- •Willing to sign the assent/permission/consent form
Exclusion Criteria
- •Underlying structural heart disease including congenital heart disease or acquired heart disease.
- •History or laboratory evidence of an underlying intestinal, metabolic, autoimmune, or renal disease that could alter the disposition of rosuvastatin or atorvastatin.
- •Underlying pathology of the gastrointestinal tract or recent surgery which would be expected to alter the rate and/or extent of drug absorption
- •Evidence of previous hypersensitivity to statin medications
- •Unwillingness or inability to have screening labs drawn
- •Refusal to participate in the study
- •Unwillingness or inability to participate in an overnight fast
- •Subjects taking drugs with interactions with statins (CYP3A4 inducers/inhibitors, OATP1B1 inducers/inhibitors) (Appendix 1)
- •Inability to swallow a tablet drug
- •For females, a positive urine beta-human chorionic gonadotropin pregnancy test result
- •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.
- •Abnormal red blood cell morphology and/or a hemoglobin less than 9 gm/dl
- •Diarrhea in the last 24 hours
Arms & Interventions
Rosuvastatin
Rosuvastatin 10mg tablet (ages 8-21 years); 1 time dose given per oral at the start of the study day.
Intervention: Rosuvastatin (Drug)
Atorvastatin
Atorvastatin 10mg tablet (ages 8-21 years); 1 time dose given per oral at the start of the study day.
Intervention: Atorvastatin (Drug)
Outcomes
Primary Outcomes
Evaluate effect of genotype (SLCO1B1) on AUC atorvastatin
Time Frame: 2 years
Evaluate effect of genotype (SLCO1BI) on Cmax rosuvastatin
Time Frame: 2 years
Evaluate effect of genotype (SLCO1B1) on AUC rosuvastatin
Time Frame: 2 years
Evaluate effect of genotype (SLCO1BI) on Cmax atorvastatin
Time Frame: 2 years
Secondary Outcomes
- Evaluate the effect of age on Cmax of rosuvastatin(2 years)
- Evaluate the effect of age on AUC of atorvastatin(2 years)
- Evaluate the effect of gender on AUC of atorvastatin(2 years)
- Evaluate the effect of sexual maturity on AUC of atorvastatin(2 years)
- Evaluate the effect of gender on AUC of rosuvastatin(2 years)
- Evaluate the effect of sexual maturity on AUC of rosuvastatin(2 years)
- Evaluate the effect of age on Ka of atorvastatin(2 years)
- Evaluate the effect of gender on Ka of atorvastatin(2 years)
- Evaluate the effect of race on Ka of rosuvastatin(2 years)
- Evaluate the effect of gender on Cmax of rosuvastatin(2 years)
- Evaluate the effect of race on Cmax of rosuvastatin(2 years)
- Evaluate the effect of race on AUC of atorvastatin(2 years)
- Evaluate the effect of sexual maturity on Ka of atorvastatin(2 years)
- Evaluate the effect of race on AUC of rosuvastatin(2 years)
- Evaluate the effect of race on Ka of atorvastatin(2 years)
- Evaluate the effect of age on Ka of rosuvastatin(2 years)
- Evaluate the effect of sexual maturity on Ka of rosuvastatin(2 years)
- Evaluate the effect of sexual maturity on Cmax of rosuvastatin(2 years)
- Evaluate the effect of age on Cmax of atorvastatin(2 years)
- Evaluate the effect of age on AUC of rosuvastatin(2 years)
- Evaluate the effect of gender on Ka of rosuvastatin(2 years)
Investigators
Jon Wagner
Pediatric Cardiologist/Clinical Pharmacology, Children's Mercy Hospital and Clinics
Children's Mercy Hospital Kansas City