Healthy Volunteer Study of Clopidogrel and Rifampicin
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      The principal research question is: Can platelet P2Y12 receptor blockade by the
      antithrombotic drug clopidogrel be significantly enhanced by coadministration of the
      antibiotic rifampicin?

      Clopidogrel is an antithrombotic drug in clinical use that reduces the risk of heart attack
      and coronary stent thrombosis. However some patients respond poorly to clopidogrel, at least
      partly because they fail to convert it effectively to its active form, and consequently are
      at higher risk of arterial thrombosis. Preliminary evidence indicates that the antibiotic
      rifampicin enhances the effectiveness of clopidogrel by increasing its conversion to its
      active form by the liver. We wish to study further the extent of rifampicin's effect on
      clopidogrel to see whether this might be useful in clinical practice.
    

Detailed description: 
      Clopidogrel is an antithrombotic drug that is licensed for the treatment and prevention of
      arterial thrombosis, such as in people admitted to hospital with heart attacks. However, some
      people fail to achieve a substantial antithrombotic effect from the drug and one important
      reason for this is that their livers do not convert clopidogrel to its active form
      effectively. Current evidence suggests that these people are less protected by clopidogrel
      and have a higher risk of arterial thrombosis than those who respond well to clopidogrel.
      Rifampicin is an antibiotic that increases the activity of liver enzymes that convert
      clopidogrel to its active form and preliminary evidence indicates that it increases the
      effectiveness of clopidogrel. This raises the possibility that rifampicin might be used with
      clopidogrel to increase its clinical effectiveness. We wish to study this interaction
      further.

      12 healthy volunteers will be recruited for this study after giving informed consent.
      Following Screening, the study will run over 28 days. Lab safety (clinical chemistry,
      haematology and urinalysis) will be undertaken on days 7, 22 and 28 in addition to screening.
      During the first visit, an intravenous cannula will be inserted into a forearm vein. Subjects
      will perform an erythromycin breath test. Subsequently, venous blood will be obtained via the
      intravenous cannula and platelet function studies will be performed and a plasma sample will
      be stored for baseline metabolite analysis. Subsequently the subjects will be administered a
      600 mg loading dose of clopidogrel (Plavix, Sanofi Pharma Bristol-Myers Squibb) and further
      blood samples will be taken over 4 hours for clopidogrel metabolite analysis and platelet
      function studies. Subjects will then take clopidogrel 75 mg daily for a further 6 days and, 4
      hours after the last dose, a further blood sample will be taken using venepuncture for
      platelet function studies and a plasma sample. After a washout period of 7 days, subjects
      will then start rifampicin 300 mg twice daily for 14 days (Rifadin, Aventis Pharma). On the
      8th day of taking rifampicin, a further intravenous cannula will be inserted, the
      erythromycin breath test will be repeated, as above, and the same regimen of clopidogrel
      administration and blood testing will be repeated, this time with co-administration of
      rifampicin.

      The data obtained will allow the following assessments: (i) comparison of the early effects
      of a 600 mg clopidogrel loading dose and late effects of clopidogrel after 7 days on platelet
      aggregation and receptor blockade; (ii) assessment of the effects of rifampicin on
      clopidogrel's action on platelet aggregation and receptor blockade following a loading dose
      and after prolonged administration of clopidogrel.
    

Intervention name(s): Clopidogrel and Rifampicin
Intervention type(s): Drug
Intervention description(s): Clopidogrel: loading dose of 600 mg, then 75 mg o.d. for up to 28 days
Rifampicin: 300 mg b.d. for up to 28 days
Other intervention name(s): Clopidorel = Plavix; Rifampicin = Rifadin
Intervention MeSH terms: Rifampin; Clopidogrel
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Thrombosis; Platelet aggregation inhibitor; Blood platelets; P2 receptor; Cytochrome P450