Lipid-lowering Therapy Individualization

Study Overview
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Brief Summary
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This clinical study will explore individual factors influencing statin pharmacokinetics in a cohort of 150 patients treated with atorvastatin.

Detailed Description
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Atorvastatin is widely prescribed for the treatment of hypercholesterolemia to prevent the risk of cardiovascular diseases, a leading death cause in industrialized countries. There exists considerable inter-individual variability in response to statins, reflected by differences in lipid-lowering effect or risk of presenting adverse drug reaction; mainly myotoxicity. A plethora of different factors (demographic, genetic, physiopathologic, environmental...) have been tested to explain this variability but it lacks of pharmacokinetic (PK) data and/or replications of observations are rare and results remain inconclusive, probably because of non-adapted designs and no-clear driven-hypothesis but also due to a lack of scientific rationale and deep mechanistic understanding. This clinical study will explore individual factors influencing statin PK in a cohort of 150 patients treated with atorvastatin. The collection of meticulous clinical PK data and a rigorous statistical analysis will allow quantifying the effect of each identified parameter on statin PK and eventually, defining a population-based PK model taking into account the combined effect of all covariates in a quantitative approach. This innovative prospectively designed clinical study will ultimately allow predicting atorvastatin PK fluctuations and anticipating any inadequate dosing in clinical care.

Official Title
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Lipid-lowering Therapy Individualization

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment with atorvastatin (any dose) Exclusion Criteria: Unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Atorvastatin<br>All patients using atorvastatin at any dose (usually ranging from 5 to 80 mg once-daily). | Drug: Atorvastatin<br>* Blood sampling for atorvastatin quantification and pharmacogenetic analysis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Atorvastatin population pharmacokinetics | Concentrations of atorvastatin acid (pmol/ml) will be measured by HPLC-MS using sparse samples obtained over the entire study period. Data will be pooled and analyzed using population pharmacokinetic modeling. The reported pharmacokinetic parameters will depend on the type of model that best fits the data. | 18 months | 
| Atorvastatin metabolites population pharmacokinetics | Concentrations of ortho-hydroxyatorvastatin (pmol/ml), para-hydroxyatorvastatin (pmol/ml) and atorvastatin lactone (pmol/ml) will be measured by HPLC-MS using sparse samples obtained over the entire study period. Data will be pooled and analyzed using population pharmacokinetic modeling. The reported pharmacokinetic parameters will depend on the type of model that best fits the data. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cholesterol | Measurement of total cholesterol, LDL cholesterol and HDL cholesterol at each visit | 18 months | 
| Creatine kinase | Measurement of creatine kinase at each visit | 18 months | 
| Occurrence of adverse drug events | Reports of adverse drug events will be recorded at each visit using a standardized questionnaire that includes the following categories : muscle cramps (grade 1 to 5), muscle pain (graded 1 to 5), rhabdomyolysis, gastro-intestinal side effects (Nauseas, diarrhea or vomitus), other side effects. | 18 months | 
| Pharmacogene genotype | Patients will be genotyped for single nucleotide polymorphisms of interest in the following genes : ABCB1, ABCC1, ABCC2, ABCC4, ABCC5, ABCG2, CYP3A4, CYP3A5, NR1I2, POR, PPARalpha, SLCO1B1, SLCO2B1, SLCO3A1. | 18 months | 
| Triglycerides | Measurement of triglyceride levels at each visit | 18 months |