8-Week PK/PD Atorvastatin Study In Children And Adolescents With Heterozygous Familial Hypercholesterolemia

• 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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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.

• Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Low-density lipoprotein cholesterol (LDL-C) measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Low-density Lipoprotein Cholesterol (LDL-C): percent (%) change from baseline by treatment over time = [LDL-C at observation minus LDL-C at Week 0] divided by LDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Total Cholesterol (TC) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Total Cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Total Cholesterol (TC) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Total cholesterol (TC): percent (%) change from baseline by treatment over time = [TC at observation minus TC at Week 0] divided by TC at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Triglycerides (TG) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Change from baseline in triglycerides measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Triglycerides (TG) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Triglycerides (TG): percent (%) change from baseline by treatment over time = [TG at observation minus TG at Week 0] divided by TG at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Change from baseline in high-density lipoprotein cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  High-density lipoprotein cholesterol (HDL-C): percent (%) change by treatment over time = [HDL-C at observation minus HDL-C at Week 0] divided by HDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Change from baseline in Apolipoprotein A-1 measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Apolipoprotein A-1 (Apo A-1): percent (%) change from baseline by treatment over time = [Apo A-1 at observation minus Apo A-1 at Week 0] divided by Apo A-1 at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Change from baseline in Apolipoprotein B measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Apolipoprotein B (Apo B): percent (%) change from baseline by treatment over time = [Apo B at observation minus Apo B at Week 0] divided by Apo B at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Change from baseline in very low-density lipoprotein-cholesterol (VLDL-C) measured in millimoles per liter (mmol/L). Change from baseline = value at observation minus baseline value. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
  Very low-density lipoprotein-cholesterol (VLDL-C): percent (%) change from baseline by treatment over time = [VLDL-C at observation minus VLDL-C at Week 0] divided by VLDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
• Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8 [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
  Brachial artery flow-mediated dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. Standardized image acquisition: brachial artery images recorded for one minute at rest, blood pressure cuff inflated to 250 mm Hg for 5 minutes with brachial artery imaged continuously throughout cuff inflation, cuff released to produce reactive hyperaemia and the brachial artery imaged continuously for 3 minutes after release. Total duration of measurement approximately 25 minutes. Change from baseline = value at observation minus baseline value.
• Percent Change From Baseline in Flow-Mediated Dilatation at Week 8 [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]

  Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%.

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• Change and % change from baseline in pharmacodynamic responses of LDL, TC, TG, HDL, VLDL, and Apo A-1, and Apo B [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Safety laboratory tests, vital signs, and adverse events [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

To evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia

• Drug: Atorvastatin
  6-10 years Tanner Stage 1 will be administered 5-mg daily dose of an atorvastatin pediatric tablet formulation. Dose may be doubled if subjects have not attained target LDL (<3.35 mmol/L) after 4-week treatment.
• Drug: Atorvastatin
  10-17 years Tanner Stage 2 will be administered 10-mg daily dose of atorvastatin tablet formulation. Dose may be doubled if subjects have not attained target LDL (<3.35 mmol/L) after 4-week treatment.

• 1
  6-10 years will be administered with atorvastatin tablet formulation with initial doses based on age cohort.
  Intervention: Drug: Atorvastatin
• 2
  10-17 years will be administered 10-mg daily dose of atorvastatin tablet formulation.
  Intervention: Drug: Atorvastatin

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)