TMC435-TiDP16-C107: This Study Measures the (Possible) Influence of TMC435 on the Activity of a Selected Set of Drug-degrading Proteins by Measuring the Blood Levels of Drugs That Have Been Taken Together With TMC435 and That Are Known to be Specifically Degraded by These Drug-degrading Proteins.
Condition: Hepatitis C; Viruses
MeSH terms: Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine whether TMC435 influences the activity of certain
      drug-degrading proteins in the human body. The drug-degrading proteins investigated in this
      study belong to the Cytochrome P (CYP) family and are called CYP1A2, CYP2C9, CYP2D6, CYP3A4
      and CYP2C19. The activity of these drug-degrading enzymes are determined by measuring the
      blood levels of a selected set of drugs, which are taken together with TMC435, and, which are
      known to be specifically degraded by a certain member of the CYP family. This selected set of
      drugs (which are taken together and therefore called a "drug cocktail") are considered as
      "probes" of these respective drug-degrading enzymes. By measuring the levels of these probes
      in human blood, the activity of these degrading enzymes are being revealed. In this way, we
      can determine if TMC435 influences in one way or another the activity of one or several of
      these selected drug-degrading proteins.
    

Detailed description: 
      This is an open-label 2-period randomized cross-over trial in 16 healthy volunteers. Eligible
      volunteers will be randomized to 2 groups. Volunteers in Group A will receive in Period 1 a
      single dose of oral midazolam and a drug cocktail alone on Day 1 and 2, respectively
      (Treatment A). In Period 2, they will receive 150 mg TMC435 once daily on Days 1-11 with a
      single dose of oral midazolam and a drug cocktail on Day 10 and 11, respectively (Treatment
      B). Volunteers in Group B will receive in Period 1 Treatment B and in Period 2 Treatment A.
      There is a period of at least 14 days between the two periods to ensure that all drugs
      administered in the previous period have been degraded and will not interfere with the
      measurements of the following period. The cocktail consists of midazolam (administered
      intravenously (abbreviated as "i.v.", which means directly injected into a blood vein.
      Injection occurs over a period of 1 minute via a a small tube (canula) that is brought into
      the blood vein to ease slow injection of the drug), omeprazole, dextromethorphan, caffeine
      and warfarin. Each of these drugs is being degraded by a specific drug-degrading protein of
      the CYP family, and are therefore ideal tools to reveal the activity of this specific
      protein. The amount of TMC435, midazolam, cocktail drugs (and some of their metabolites, i.e.
      degradation products) in blood will be assessed on selected time points. Safety and
      tolerability of the coadministration of TMC435 and oral midazolam and of TMC435 and the drug
      cocktail will be assessed throughout the trial. Safety and tolerability follow up includes
      the assessment of several blood parameters (blood cells, biochemical activity of certain
      proteins, minerals, coagulation factors, …), of several parameters in urine (blood cells,
      proteins, glucose, …) and of the cardiac activity (via electrocardiogram, blood pressure,
      pulse rate). Healthy volunteers will receive treatments in either A-B sequence or B-A
      sequence. Treatment A consists of oral midazolam (0.075 mg/kg) on Day1 and cocktail (*) on
      Day2. Treatment B consists of TMC435 (150 mg q.d.) on Day1-11, oral midazolam (0.075 mg/kg)
      on Day10 and cocktail (*) on Day11. (*) Cocktail: 0.025 mg/kg midazolam (i.v.),
      dextromethorphan (30 mg, orally), caffeine (150 mg, orally), omeprazole (40 mg, orally) and
      warfarin (10 mg, orally) supplemented with vitamin K (10 mg, orally)
    

Intervention name(s): TMC435
Intervention type(s): Drug
Intervention MeSH terms: Simeprevir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: TMC435350; HCV; Hepatitis C; TMC435; protease inhibitor; CYP; Cooperstown 5+1 cocktail