Healthy Volunteers
Conditions
Keywords
Orfadin, Nitisinone, Bioequivalence, Bioavailability
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.
Interventions
DRUGNitisinone, capsule
DRUGNitisinone, suspension
Sponsors
Swedish Orphan Biovitrum
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Netherlands
Participant flow
Recruitment details
First subject screened: 29 August 2012 Last subject last visit: 25 October 2012.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study All treatment arms | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 35 years STANDARD_DEVIATION 12 |
| Region of Enrollment Netherlands | 12 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 2 / 12 | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions.
Time frame: 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.
Population: Full analysis set was used; subjects with available PK data for at least one of the treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Orfadin Capsules, Fasting | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions. | 403 uM*h |
| Orfadin Suspension, Fasting | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions. | 346 uM*h |
90% CI: [0.81, 0.91]ANOVA
Primary
The Maximum Serum Concentration (Cmax) During Fasting Conditions.
Time frame: 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.
Population: Full analysis set was used; subjects with available PK data for at least one of the treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Orfadin Capsules, Fasting | The Maximum Serum Concentration (Cmax) During Fasting Conditions. | 10213 nM |
| Orfadin Suspension, Fasting | The Maximum Serum Concentration (Cmax) During Fasting Conditions. | 9741 nM |
90% CI: [0.85, 1.07]ANOVA
Secondary
Apparent Volume of Distribution (Vz/F)
Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time frame: 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.
Population: Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Orfadin Capsules, Fasting | Apparent Volume of Distribution (Vz/F) | 9.80 L |
| Orfadin Suspension, Fasting | Apparent Volume of Distribution (Vz/F) | 12.2 L |
| Orfadin Suspension, With Food | Apparent Volume of Distribution (Vz/F) | 12.8 L |
Secondary
AUC From Time Zero to Infinity
Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time frame: 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.
Population: Per-protocol set (bioequivalence) was used for fasted treatment groups and per-protocol set (food effect) for fed treatment group (all subjects with available PK data)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Orfadin Capsules, Fasting | AUC From Time Zero to Infinity | 633 h*uM |
| Orfadin Suspension, Fasting | AUC From Time Zero to Infinity | 559 h*uM |
| Orfadin Suspension, With Food | AUC From Time Zero to Infinity | 577 h*uM |
Secondary
Oral Clearance (CL/F)
Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time frame: 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.
Population: Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Orfadin Capsules, Fasting | Oral Clearance (CL/F) | 0.145 L/h |
| Orfadin Suspension, Fasting | Oral Clearance (CL/F) | 0.160 L/h |
| Orfadin Suspension, With Food | Oral Clearance (CL/F) | 0.158 L/h |
Secondary
Terminal Half-life
Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time frame: 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.
Population: Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Orfadin Capsules, Fasting | Terminal Half-life | 48.7 hours |
| Orfadin Suspension, Fasting | Terminal Half-life | 53.6 hours |
| Orfadin Suspension, With Food | Terminal Half-life | 54.3 hours |
Secondary
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.
Time frame: 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.
Population: Full analysis set was used; subjects with available PK data for at least one of the treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Orfadin Capsules, Fasting | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) | 346 uM*h |
| Orfadin Suspension, Fasting | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) | 350 uM*h |
90% CI: [0.96, 1.07]ANOVA
Secondary
The Maximum Serum Concentration (Cmax)
Measured for the Orfadin suspension treatment arms- both fasting and with food.
Time frame: 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.
Population: Full analysis set was used; subjects with available PK data for at least one of the treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Orfadin Capsules, Fasting | The Maximum Serum Concentration (Cmax) | 9741 nM |
| Orfadin Suspension, Fasting | The Maximum Serum Concentration (Cmax) | 7808 nM |
90% CI: [0.71, 0.9]ANOVA
Secondary
Time to Reach C-Max (t-Max)
Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
Time frame: 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.
Population: Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Orfadin Capsules, Fasting | Time to Reach C-Max (t-Max) | 3.50 hours |
| Orfadin Suspension, Fasting | Time to Reach C-Max (t-Max) | 0.38 hours |
| Orfadin Suspension, With Food | Time to Reach C-Max (t-Max) | 8.00 hours |