Conditions: Hereditary Tyrosinemia, Type I
Keywords: HT-1 Tyrosinemia Nitisinone Bioequivalence Healthy Volunteer Orfadin
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine whether Nitisinone 10 mg Tablets (Test Product 1 (TP1)) and Nitisinone 10 mg Tablets High Compritol (Test Product 2 (TP2)) are bioequivalent to the reference product Orfadin 10 mg capsules.

Detailed description:
The specific aim is to conduct a randomized, single dose, three-period cross-over bioequivalence (BE) study in at least 18 healthy male and female subjects at a single study center to evaluate the in vivo performance of Nitisinone 10 mg Tablet (Test Product 1) and Nitisinone 10 mg Tablet High Compritol (Test Product 2) to the reference product Orfadin 10 mg capsules.

The pharmacokinetics (PK) of Test Product 1 and 2 compared to the reference product, will be determined and compared in healthy volunteers.

The modified version of Nitisinone Tablet (Test Product 2, higher glyceryl dibehenate (Compritol 888)) was administered to determine the acceptance limit of the dissolution profile for Nitisinone tablets with a longer dissolution time (Test Product 2) since the dissolution time of Nitisinone tablets (Test Product 1) lengthened over time under accelerated study conditions. The hypothesis is that should bioequivalence between Test Product 1 and Test Product 2 be demonstrated then it is concluded that the prolonged dissolution time had no impact on the bioequivalence of Nitisinone tablets.

A total of 24 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 one of the three treatment sequence groups and, on each occasion, receive one of the following: Nitisinone 10 mg Tablet, Nitisinone 10 mg High Compritol Tablet and Orfadin 10 mg hard capsules (reference listed drug, (RLD)). 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).

The primary endpoints will be the maximum blood concentration (Cmax) and the area under the curve (AUC) from time zero to 120 hours post-dose.

For the FDA, bioequivalence of the test and reference products will be assessed on the basis of the 90% confidence intervals for estimates of the geometric mean ratios between the primary PK parameters of the test and reference products using an analysis of variance considering the bioequivalence range of 80.00% to 125.00% for Cmax and AUC(0-120).

For Health Canada, bioequivalence of the test and reference products will be assessed on the basis of the 90% confidence interval for estimate of the geometric mean ratio between the primary PK parameter AUC(0-120) of the test and reference products using an analysis of variance considering the bioequivalence range of 80.00% to 125.00% and the point estimate of the geometric mean ratio of the primary PK parameter Cmax considering the bioequivalence range of 80.00% to 125.00%.

Arms:
arm 1: Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period. arm 2: Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 2) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period. arm 3: Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period. arm 4: Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 3, and under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period. arm 5: Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 2, and 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period. arm 6: Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 2, 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.

Interventions: intervention 1: Nitisinone intervention 2: Nitisinone 10 mg Tablet High Compritol intervention 3: Orfadin
Intervention descriptions: intervention 1: A single oral dose of Nitisinone 10 mg tablet will be administered in fasted state. intervention 2: A single oral dose of Nitisinone 10 mg High Compritol tablet will be administered in fasted state. intervention 3: A single oral dose of Orfadin 10 mg hard capsule will be administered in fasted state.

Protocol document: