To evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
39
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.
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.
Pfizer Investigational Site
Québec, Quebec, Canada
Pfizer Investigational Site
Athens, Greece
Pfizer Investigational Site
Oslo, Norway
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)
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.
Time frame: Week 2, Week 4, Week 6, Week 8
Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F)
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.
Time frame: Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
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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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Total Cholesterol (TC)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Total Cholesterol (TC)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Triglycerides (TG)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Triglycerides (TG)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Apolipoprotein B (Apo B)
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.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Apolipoprotein B (Apo B)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
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 \[optional at Weeks 2 and 6\]).
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8
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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Flow-Mediated Dilatation at Week 8
Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. .
Time frame: Baseline, Week 8