Drug-drug Interaction Study in Healthy Male Volunteers Following the Administration of Pantoprazole and Rosuvastatin
Condition: Drug Interaction Potentiation
Study type: Interventional
Phase: Phase 1

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

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.
    

Intervention name(s): Rosuvastatin, Pantoprazole
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Crestor 10 mg; Pantoloc 40 mg
Intervention MeSH terms: Pantoprazole; Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science