Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)
Condition: Hereditary Tyrosinemia, Type I
MeSH terms: Tyrosinemias
Intervention: Nitisinone; Nitisinone Baked Tablet; Orfadin
Intervention description: A single oral dose of Nitisinone 10 mg Tablet will be administered.; A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.; A single oral dose of Orfadin 10 mg hard capsule will be administered.
Intervention MeSH terms: Nitisinone
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: HT-1; Tyrosinemia; Nitisinone; Bioavailability; Healthy Volunteer; Food-Effect

Summary:

      The purpose of this study is to determine whether Nitisinone 10 mg Tablets (Test Product 1)
      and Nitisinone 10 mg Tablets 'Baked' for 6 months @ 40°C/75% RH (Test Product 2) are
      bioequivalent to the reference product Orfadin 10 mg hard capsules.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Healthy male and female subjects, 18 to 55 years (both inclusive) at signing of
             informed consent.

          -  Body Mass Index (BMI) between 18.5 and 30 kg/m2 (inclusive).

          -  Body mass not less than 50 kg.

          -  Medical history, vital signs, physical examination, standard 12-lead electrocardiogram
             (ECG) and laboratory investigations must be clinically acceptable or within laboratory
             reference ranges for the relevant laboratory tests, unless the investigator considers
             the deviation to be irrelevant for the purpose of the study.

          -  Non-smokers.

          -  Females, if:

        Of childbearing potential, the following conditions are to be met:

          -  Negative pregnancy test If this test is positive, the subject will be excluded from
             the study. In the rare circumstance that a pregnancy is discovered after the subject
             received IMP, every attempt must be made to follow her to term.

          -  Not lactating

          -  Abstaining from sexual activity (if this is the usual lifestyle of the subject) or
             must agree to use an accepted method of contraception, and agree to continue with the
             same method throughout the study Examples of reliable methods of contraception include
             non-hormonal intrauterine device, and barrier methods combined with an additional
             contraceptive method. In this study the concomitant use of hormonal contraceptives is
             NOT allowed. Other methods, if considered by the investigator as reliable, will be
             accepted.

          -  Written consent given for participation in the study.

        Exclusion Criteria:

          -  Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional
             or intellectual problems likely to limit the validity of consent to participate in the
             study or limit the ability to comply with protocol requirements.

          -  Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol
             per week for females.

          -  Consumption of more than 5 cups of coffee (or equivalent amounts of caffeine) per day.

          -  Regular exposure to substances of abuse (other than alcohol) within the past year.

          -  Use of any medication, prescribed or over-the-counter or herbal remedies, within 2
             weeks before the first administration of IMP except if this will not affect the
             outcome of the study in the opinion of the investigator.

        In this study the concomitant use of hormonal contraceptives is NOT allowed.

          -  Participation in another study with an experimental drug, where the last
             administration of the previous IMP was within 8 weeks (or within 10 elimination
             half-lives for chemical entities or 2 elimination half-lives for antibodies or
             insulin), whichever is the longer) before administration of IMP in this study, at the
             discretion of the investigator.

          -  Treatment within the previous 3 months before the first administration of IMP with any
             drug with a well-defined potential for adversely affecting a major organ or system.

          -  A major illness during the 3 months before commencement of the screening period.

          -  History of hypersensitivity or allergy to the IMP or its excipients or any related
             medication.

          -  History of bronchial asthma or any other bronchospastic disease.

          -  History of convulsions.

          -  History of porphyria.

          -  Relevant history or laboratory or clinical findings indicative of acute or chronic
             disease, likely to influence study outcome.

          -  Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the
             first administration of IMP.

          -  Diagnosis of hypotension made during the screening period.

          -  Diagnosis of hypertension made during the screening period or current diagnosis of
             hypertension.

          -  Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening
             period, either supine or standing.

          -  Positive testing for human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C.

          -  Positive urine screen for drugs of abuse. In case of a positive result the urine
             screen for drugs of abuse may be repeated once at the discretion of the investigator.

          -  Positive urine screen for tobacco use.

          -  Positive pregnancy test.

          -  Female subjects that are pregnant or breastfeeding.

          -  Difficulty in swallowing.

          -  Any specific investigational product safety concern.

          -  Vulnerable subjects, e.g. persons in detention.

          -  Subjects with current keratopathy, or other clinically significant abnormalities found
             by slit-lamp examination (cataracts) at the discretion of the investigator.

          -  Concomitant use of medications that are metabolized by CYP2C9 (ibuprofen, diclofenac
             and indomethacin).