Lipid-lowering Therapy Individualization

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

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Atorvastatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Treatment with atorvastatin (any dose)

Exclusion Criteria:

• Unable to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Université Catholique de Louvain
• Collaborators: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Investigators: Principal Investigator: Jean-Luc Balligand, MD, PhD, Cliniques Universitaires Saint-Luc

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2017
• Primary Completion (Actual): August 27, 2019
• Study Completion (Actual): August 27, 2019

Study Registration Dates

• First Submitted: June 27, 2018
• First Submitted That Met QC Criteria: July 19, 2018
• First Posted (Actual): July 27, 2018

Study Record Updates

• Last Update Posted (Actual): September 3, 2019
• Last Update Submitted That Met QC Criteria: August 30, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 2016/26OCT/471

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes