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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Nitisinone, capsule; Drug: Nitisinone, suspension

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands
    • Pharmaceutical Research Associates Group B.V (PRA)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Orfadin capsules, fasting; Orfadin capsules, single dose, 30 mg	Drug: Nitisinone, capsule
EXPERIMENTAL: Orfadin suspension, fasting; Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)	Drug: Nitisinone, suspension
EXPERIMENTAL: Orfadin suspension, with food; Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL)	Drug: Nitisinone, suspension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): October 1, 2012
• Study Completion (ACTUAL): October 1, 2012

Study Registration Dates

• First Submitted: September 7, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (ESTIMATE): September 11, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): March 17, 2014
• Last Update Submitted That Met QC Criteria: February 20, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Bioequivalence; Bioavailability; Nitisinone; Orfadin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nitisinone
• Other Study ID Numbers: Sobi.NTBC-001