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

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: Nitisinone, capsule
Drug: Nitisinone, suspension

Registration Number: NCT01682538

Lead Sponsor: Swedish Orphan Biovitrum

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 12

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Orfadin capsules, fasting	Nitisinone, capsule	Orfadin capsules, single dose, 30 mg
Orfadin suspension, fasting	Nitisinone, suspension	Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)
Orfadin suspension, with food	Nitisinone, suspension	Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL)

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h)	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.	Measured for the Orfadin suspension treatments arms- both fasting and with food.
The Maximum Serum Concentration (Cmax)	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.	Measured for the Orfadin suspension treatment arms- both fasting and with food.
AUC From Time Zero to Infinity	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.	Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time to Reach C-Max (t-Max)	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.	Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Terminal Half-life	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.	Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Oral Clearance (CL/F)	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.	Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Apparent Volume of Distribution (Vz/F)	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.	Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.