Bioequivalence of Orfadin Suspension Compared to Orfadin Capsules, and the Effect of Food on the Bioavailability of the Suspension

Study Overview
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Brief Summary
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The study is primarily being performed in order to demonstrate bioequivalence between the Orfadin (nitisinone) suspension and the marketed capsule formulation. The study will also contain a comparison of the bioavailability of the suspension given with food and on an empty stomach.

Detailed Description
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This is an open, randomized 3-way crossover study in 12 healthy volunteers. Subjects will receive single oral 30-mg doses of nitisinone as a suspension (fasting and with food) and as hard gelatin capsules (fasting only). There will be a 2-week washout period between the doses. There will be a screening visit within 3 weeks prior to the first dose. During each treatment period, subjects will be admitted to the clinic from the afternoon on the day before drug administration (i.e., on Day -1) and remain at the clinic until the 48-hour post-dose blood sample has been collected in the morning of Day 3. They will then return for ambulatory visit in the morning of Day 4 (72-hour sample). A follow-up visit will take place 7-14 days after the last dose.

Official Title
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A Study to Evaluate the Bioequivalence of Orfadin Suspension 4 mg/mL Compared to Orfadin Capsules 10 mg, and the Effect of Food on the Bioavailability of the Suspension. An Open-label, Randomized, Cross-over, Single-dose Study in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Nitisinone, capsule
* Drug: Nitisinone, suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male volunteers Age: 18-55 years, inclusive BMI: 18,5-30,0 kg/m2, inclusive Exclusion Criteria: heavy smokers Consumption of more than 4 cups of coffee per day. History of drug and/or alcohol abuse. Positive drug screen or alcohol breath test. Positive screens for hepatitis B surface antigen, hepatitis C antibodies and human immunodeficiency virus (HIV) 1-2 antibodies. Enrollment in another concurrent clinical study Intake of an investigational medicinal product within three months prior to inclusion in this study. Donation of more than 50 mL of blood within 60 days prior to drug administration Donation of more than 1,5 liters of blood in the 10 months prior to first drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Orfadin capsules, fasting<br>Orfadin capsules, single dose, 30 mg | Drug: Nitisinone, capsule<br> <br> |
| Experimental: Orfadin suspension, fasting<br>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL) | Drug: Nitisinone, suspension<br> <br> |
| Experimental: Orfadin suspension, with food<br>Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL) | Drug: Nitisinone, suspension<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions. |  | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| The Maximum Serum Concentration (Cmax) During Fasting Conditions. |  | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) | Measured for the Orfadin suspension treatments arms- both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| The Maximum Serum Concentration (Cmax) | Measured for the Orfadin suspension treatment arms- both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| AUC From Time Zero to Infinity | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| Time to Reach C-Max (t-Max) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| Terminal Half-life | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| Oral Clearance (CL/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 
| Apparent Volume of Distribution (Vz/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orfadin, Nitisinone, Bioequivalence, Bioavailability