A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers
Condition: Drug Drug Interaction
Study type: Interventional
Phase: Phase 1

Summary: 
      An open-label, non-randomized, 2-arm, 2-period fixed sequence phase 1 study to evaluate the
      potential inhibition of nitisinone on cytochrome P450 2C9, 2D6, and 2E1 and the organic anion
      transporters OAT1 and OAT3 in healthy volunteers
    

Detailed description: 
      This is an open-label, non-randomized, 2-arm, 2-period fixed-sequence drug-drug interaction
      study in a total of 36 (18 in each arm) male and female healthy volunteers.

      The study consists of: Screening, Period 1 (substrates only), Period 2 (substrates +
      nitisinone) and Follow-up. In the screening period, subjects will be assessed for
      eligibility. Eligible subjects will be assigned to one of two treatment arms. In Arm A, the
      potential inhibition of nitisinone on CYP2C9, CYP2D6, and CYP2E1 will be investigated. In Arm
      B, the possible combined effect of nitisinone on the renal transporters OAT1 and OAT3 will be
      investigated.

      In Period 1, the subjects will receive a single dose of a CYP cocktail of 3 substrates (Arm
      A) or an OAT1/OAT3 substrate (Arm B). Substrate plasma concentrations will be measured for
      determination of substrate PK; for up to 48 hours in Arm A and for 8 hours in Arm B.

      During Period 2, the treatment and assessments will vary slightly between the 2 treatment
      arms. Nitisinone will be administered for 14 days, without co-administration of any
      substrate, in order to reach steady state and the recommended target plasma concentration,
      before the interaction with the substrates is studied.

      In Arm A, Period 2, subjects will receive nitisinone for 16 consecutive days (14 days on
      nitisinone only and two days on nitisinone + substrate). Nitisinone steady state PK will be
      determined based on plasma and urine samples collected during one dosage interval at steady
      state, on the day before co-administration of the substrates. Nitisinone will then be
      administered together with the CYP substrates, and plasma samples for determination of their
      PK will be collected as in Period 1. There will be a final nitisinone dose on the day after
      substrate administration in order to maintain therapeutic levels throughout the 48-hour
      sampling period.

      In Arm B, Period 2, subjects will receive nitisinone for 15 consecutive days (14 days on
      nitisinone only and one day on nitisinone + substrate). No nitisinone steady state PK
      characterization will be conducted in this arm. On the last treatment day, the subjects will
      receive nitisinone together with the OAT1/OAT3 substrate. This will be followed by 8 hours of
      blood sampling for determination of substrate PK.
    

Intervention name(s): Nitisinone in Arm A; Tolbutamide; Metoprolol; Chlorzoxazone; Furosemide; Nitisinone in Arm B
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 4 capsules of 20 mg nitisinone (80 mg) is given once daily for 17 days.; A 500 mg tablet is given as single oral dose 2 weeks apart.; A 50 mg tablet of metoprolol tartrate is given as single oral dose 2 weeks apart.; A 250 mg tablet is given as single oral dose 2 weeks apart.; A single intravenous dose of 20 mg administered as an i.v. infusion is given 2 weeks apart.; 4 capsules of 20 mg nitisinone (80 mg) is given once daily for 16 days.
Other intervention name(s): Orfadin; Orfadin
Intervention MeSH terms: Tolbutamide; Metoprolol; Furosemide; Chlorzoxazone; Nitisinone
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Basic Science