Bioequivalence Study of Two Nitisinone Formulations Compared to Orfadin
Condition: Hereditary Tyrosinemia, Type I
MeSH terms: Tyrosinemias
Study type: Interventional
Phase: Phase 1

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%.
    

Intervention name(s): Nitisinone; Nitisinone 10 mg Tablet High Compritol; Orfadin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A single oral dose of Nitisinone 10 mg tablet will be administered in fasted state.; A single oral dose of Nitisinone 10 mg High Compritol tablet will be administered in fasted state.; A single oral dose of Orfadin 10 mg hard capsule will be administered in fasted state.
Intervention MeSH terms: Nitisinone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: HT-1; Tyrosinemia; Nitisinone; Bioequivalence; Healthy Volunteer; Orfadin