Bioavailability Food-Effect Study of an Oral Nitisinone Formulation to Treat Hereditary Tyrosinemia (HT-1)

A Single Center, Single-Dose, Open-Label, Randomized Study to Compare the Bioavailability of an Oral Test Formulation Containing Nitisinone 10 mg in at Least 16 Healthy Male and Female Subjects Under Fasting and Fed Conditions

The purpose of this study is to compare the bioavailability of the Test Product, Nitisinone 10 mg Tablet, under fasting and fed conditions (food-effect).

The specific aim is to conduct a randomized, single dose, two-period crossover bioavailability study in at least 16 healthy male and female subjects at a single study center to evaluate the in vivo performance of Test Product, Nitisinone 10 mg Tablet, under fasting and fed conditions.

The study in healthy male and female volunteers is designed to establish a pharmacokinetic (PK) profile under fed and fasting conditions for the orally administered Test Product, Nitisinone 10 mg Tablets.

A total of 20 healthy female and male volunteers (age 18 to 55 years old) will be entered into the study. Volunteers will be determined to be free of significant medical conditions as assessed by medical history, physical examination, and blood and urine tests. Volunteers will be randomly allocated to receive the Test Product under fasting or fed conditions.

There will be a minimum 23 calendar days washout between treatments. Blood samples will be collected at pre-dose (0 hours) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 2 hours and 30 minutes, 3 hours, 3 hours and 30 minutes, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours and 120 hours post-dose (total: 21 samples per treatment period).

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.
• Subjects must be willing to consume the meal prescribed with administration of the IMP in full and within the required time.

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 investigational medicinal product (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).