Drug-drug Interaction Study in Healthy Male Volunteers Following the Administration of Pantoprazole and Rosuvastatin

This is a single-center, randomized, 2-period, 2-sequence, cross-over study.

Study Overview

• Status: Completed
• Conditions: Drug Interaction Potentiation
• Intervention / Treatment: Drug: Rosuvastatin, Pantoprazole

Detailed Description

Background:

Notions used to describe drug disposition are being reviewed as the roles of drug membrane transporters are being discovered. In the near past, simple biophysical principles - lipophilicity and passive diffusion - were used to explain drug absorption, distribution and elimination. Today, with more than 367 genes known in humans, membrane transporters occupy a much central role.

Rational:

Drug influx/efflux transporters are expressed in various organs with variable activities and their presence increases (influx) or decreases (efflux) the intracellular concentration of a drug in a specific organ. Therefore, intersubject variability in the activity of these transporters due to genetic polymorphisms or concomitant drug treatments can explain intersubject variability in drug actions.

Rosuvastatin is an HMG-CoA reductase inhibitor and a substrate of OATPs and BCRP. There is not much information on the transporter-mediated disposition of rosuvastatin. Literature suggests that rosuvastatin is a transporter substrate of the influx OATP1B1, 1B3 and 2B1 as well as the efflux BCRP. The efflux of rosuvastatin by BCRP would be of major importance in the hepatocytes. BCRP would be responsible of the excretion of 30% of the unchanged drug in the bile. To confirm this hypothesis and identify patients at risk of toxicity with rosuvastatin, we want to perform a drug-drug interactions study with an inhibitor of BCRP namely, pantoprazole. With this approach, we will confirm if rosuvastatin is a real substrate of BCRP as suggested in the literature.

Methodology:

To determine changes induced by the administration of pantoprazole on the pharmacokinetics of rosuvastatin in healthy volunteers 16 healthy volunteers will be administered a single dose of rosuvastatin with and without (placebo) pantoprazole.

Urine and plasma analysis will be performed by LC-MSMS. Pharmacokinetics analysis will be performed. Plasma and urine concentrations of rosuvastatin will be analysed using a noncompartmental method. Pharmacokinetic parameters calculated in this study will be Cmax, Tmax, AUC0-72, AUC0-∞, Kel, T1/2β, CL/F, CLr, and Ae.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W1T7
      • Centre Hospitalier de l'Universite de Montreal (CHUM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Vital Signs, EKG and Clinical Laboratory Values within the normal range
• Body mass index (BMI) [20-29kg/m2]
• Caucasian male
• Age between [18-55]
• Healthy by physical exam
• Non or ex-smoker

Exclusion Criteria:

• Presence or history of intolerance or hypersensibility to proton pump inhibitors or HMG-CoA reductase inhibitors.
• Significant illness. History of cardiovascular, kidney, liver or gastrointestinal disease. Presence of cardiovascular, pulmonary, hematologic, neurologic, psychiatric, endocrine, immunologic or dermatologic disease.
• consumption of an investigational product or donation of blood in the previous 28 days preceding the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Rosuvastatin, Pantoprazole; Rosuvastatin, 10 mg tablets, single dose on the morning Concomitant drug: Pantoprazole; 40 mg tablets, 2 single doses administered 1 hour before rosuvastatin and 23 hours after rosuvastatin administration. A placebo is given on the other period as a crossover design study.; Other Names: Crestor 10 mg; Pantoloc 40 mg
Active Comparator: Pantoprazole; two-arm study: 2-period, 2-sequence, cross-over study.Volunteers will be administered either sequence 1 or sequence 2 randomly.	Drug: Rosuvastatin, Pantoprazole; Rosuvastatin, 10 mg tablets, single dose on the morning Concomitant drug: Pantoprazole; 40 mg tablets, 2 single doses administered 1 hour before rosuvastatin and 23 hours after rosuvastatin administration. A placebo is given on the other period as a crossover design study.; Other Names: Crestor 10 mg; Pantoloc 40 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine changes induced by pantoprazole administration on the pharmacokinetics of rosuvastatin in healthy volunteers.	Rosuvastatin will be administered with and without pantoprazole.	2 weeks

Collaborators and Investigators

• Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Collaborators: Centre de Recherche du Centre Hospitalier de l'Université de Montréal
• Investigators: Principal Investigator: Pavel Hamet, M.D., Ph.D., Centre Hospitalier de l'Universite de Montreal (CHUM)

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: May 25, 2010
• First Submitted That Met QC Criteria: June 16, 2010
• First Posted (Estimate): June 17, 2010

Study Record Updates

• Last Update Posted (Estimate): December 15, 2011
• Last Update Submitted That Met QC Criteria: December 14, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Rosuvastatin Calcium; Pantoprazole
• Other Study ID Numbers: CE 09.252