A 8-Week, Open-Label, Phase 1 Study To Evaluate Pharmacokinetics, Pharmacodynamics, Safety And Tolerability Of Atorvastatin In Children And Adolescents With Heterozygous Familial Hypercholesterolemia
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 39
- Locations
- 1
- Primary Endpoint
- Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)
Study Overview
Brief Summary
To evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Parallel
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 6 Years to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Genetically confirmed heterozygous familial hypercholesterolemia (HeFH) with LDL greater or equal 4 mmol/L at baseline
Exclusion Criteria
- •Evidence or history of clinically significant diseases, homozygous familial hypercholesterolemia (FH)
Arms & Interventions
1
6-10 years will be administered with atorvastatin tablet formulation with initial doses based on age cohort.
Intervention: Atorvastatin (Drug)
2
10-17 years will be administered 10-mg daily dose of atorvastatin tablet formulation.
Intervention: Atorvastatin (Drug)
Outcomes
Primary Outcomes
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)
Time Frame: Week 2, Week 4, Week 6, Week 8
Parent-metabolite population PK model built using sparse blood samples from both Tanner Stage 1 and Tanner Stage 2+. Blood sampling times: Weeks 2 and 6: single sample between 4 and 12 hours postdose; Weeks 4 and 8: predose, 1 hour, and 2 hours postdose. Plasma samples were analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using a validated, sensitive, and specific high-performance liquid chromatography tandem mass spectrometric method. Data presented are the result of the model used.
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F)
Time Frame: Week 2, Week 4, Week 6, Week 8
Parent-metabolite population PK model built using sparse blood samples from Tanner Stages 1 and 2+. Sampling times: Weeks 2 + 6: single sample between 4 -12 hours postdose; Weeks 4 + 8: predose, 1 + 2 hours postdose. Plasma samples analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using validated, sensitive, specific high-performance liquid chromatography tandem mass spectrometric method. Vc/F value based on 70 kg body weight. Parameter estimation uncertainty (95% CI) by non-parametric bootstrap analysis. Data presented are result of model used.
Secondary Outcomes
- Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Total Cholesterol (TC)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Apolipoprotein B (Apo B)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Total Cholesterol (TC)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Triglycerides (TG)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Triglycerides (TG)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8(Baseline, Week 8)
- Percent Change From Baseline in Apolipoprotein B (Apo B)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Percent Change From Baseline in Flow-Mediated Dilatation at Week 8(Baseline, Week 8)