Healthy Volunteers Bioequivalence or Bioavailability Study
Conditions
Keywords
bioequivalence, bioavailability, pharmacokinetics, Phase I, AZD6244, cancer
Brief summary
A Study to assess, against a reference selumetinib capsule, if the drug levels of a variant of selumetinib capsule are comparable, and to assess how drug levels differed in another variant of Selumetinib in Healthy Male Volunteers.
Interventions
3 blue capsules of 25 mg given as a single dose
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1.Provision of written informed consent 2.Healthy male volunteers aged 18 to 45 years 3.Calculated creatinine clearance (CrCL) \>50 mL/minute using the Cockcroft-Gault formula 4.Healthy volunteers with sexual partners who could become pregnant should agree to use 2 highly effective methods of contraception. Healthy volunteers with sexual partners who are pregnant should agree to use an effective method of contraception (barrier method) from the first administration until 12 weeks after the last administration of the investigational product. Healthy volunteers should avoid sperm donation during the study and for 12 weeks after the last administration of the investigational product 5.Use no nicotine containing products for at least 3 months prior to screening 6.For inclusion in the genetic component of the study, healthy volunteers provide written informed consent for genetic research.
Exclusion criteria
1.Healthy male volunteers of Japanese or non Japanese Asian, or Indian ethnicity 2.Any one parent or grandparent (maternal or paternal) is Japanese or non-Japanese Asian or Indian 3.Involvement in the planning and/or conduct of the study. 4.Previous randomisation to treatment in the present study 5.Participation in another clinical study within 3 month before Visit 1, or participation in a method development study 1 month before Visit 1. 6.Current or past history of central serous retinopathy or retinal vein thrombosis, intraocular pressure greater than 21 mmHg or uncontrolled glaucoma 7.Any clinically significant disease or disorder that may put the healthy volunteer at risk because of participation in the study, influence the result of the study or influence the healthy volunteer's ability to participate in the study 8.Any clinically relevant abnormal findings in physical examination, haematology, clinical chemistry, urinalysis, vital signs or 12-lead ECG at Visit 1, which may put the healthy volunteer at risk because of his participation in the study. 9.Use of prescribed medications and over-the-counter drugs (including herbal remedies) known to have moderate or strong cytochrome P450 (CYP) 3A4 or CYP2C19 inducer or inhibitory effects from 30 days prior to the first administration of investigational product until the follow up visit 10.Use of any other prescribed medications and over-the-counter drugs (including herbal remedies, vitamins and minerals) within 2 weeks or 5 times the half life, whichever is longer, of the respective drug prior to Visit 2, with the exception of occasional use of acetaminophen (paracetamol or TYLENOL®) and over-the-counter adrenergic nasal spray for relief of nasal congestion. No medications known to prolong the QT/corrected QT interval (QTc) interval are allowed 11.Excessive intake of caffeine containing drinks or food. 12.Any intake of grapefruit and Seville oranges or other products containing grapefruit or Seville oranges within 7 days of the first admission 13.A definite or suspected personal history of intolerance or hypersensitivity to drugs and/or their excipients 14.Plasma donation or any blood donation/blood loss greater than 500 mL during the 3 months prior to screening 15.History of, or current alcohol or drug abuse. 16.A suspected/manifested infection according to the International Air Transport Association (IATA) Categories A and B infectious substances 17.Healthy male volunteers who do not agree to use at least 2 effective methods of contraception 18.Positive results at screening for human immunodeficiency virus (HIV) and/or hepatitis B and/or hepatitis C 19.Planned inpatient surgery, dental procedure or hospitalisation during the study 20.Healthy male volunteers who, in the opinion of the Principal Investigator, should not participate in the study 21.Healthy male volunteers with a LVEF \<55% 22.Previous bone marrow transplant 23.Whole blood transfusion within 120 days of the genetic sample collection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4). | The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the maximum observed plasma concentration (Cmax) of selumetinib in healthy volunteers. |
| Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4). | The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) of selumetinib in healthy volunteers. |
| Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4). | The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC from time zero to the time of the last quantifiable concentration (AUC\[0-t\]) of selumetinib in healthy volunteers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the Cmax of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C). |
| Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the Cmax of selumetinib in healthy volunteers. |
| The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t) | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the AUC(0-t) of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C). |
| Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | The relative bioavailability of the TPGS capsules variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC of selumetinib in healthy volunteers. |
| Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4). | The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC\[0-t\] of selumetinib in healthy volunteers. |
Countries
United Kingdom
Participant flow
Recruitment details
48 healthy adult males were enrolled in this single centre, randomised, open label, 3-period, 3-treatment and 6-sequence crossover study from 24 February 2015 to study completion on 30 April 2015. Subjects attended the clinical study unit for at least 1 screening visit and 3 treatment periods.
Pre-assignment details
48 subjects received at least 1 of the 3 treatments and 45 completed all 3 treatment periods. There was a washout period of 7 to 10 days between administrations. A follow-up visit occurred 7 days after the last administration of the third treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study All subjects received at least 1 dose of selumetinib. Subjects were randomised in a crossover fashion to receive 1 of 3 treatments during each treatment period: Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 2 | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 3 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 31 years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 48 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 | 12 / 46 | 12 / 48 | 9 / 45 |
| serious Total, serious adverse events | 0 / 46 | 0 / 48 | 0 / 45 |
Outcome results
Primary
Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC]
The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | 3750 ng * hour per mL (ng*h/mL) | Geometric Coefficient of Variation 24.1 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | 905 ng * hour per mL (ng*h/mL) | Geometric Coefficient of Variation 32.6 |
90% CI: [22.62, 26.03]
Primary
Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)]
The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC from time zero to the time of the last quantifiable concentration (AUC\[0-t\]) of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | 3670 ng*h/mL | Geometric Coefficient of Variation 24 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | 814 ng*h/mL | Geometric Coefficient of Variation 32.2 |
90% CI: [20.65, 23.69]
Primary
Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax]
The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the maximum observed plasma concentration (Cmax) of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The Pharmacokinetic (PK) analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | 1330 nanograms per millilitre (ng/mL) | Geometric Coefficient of Variation 36.6 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | 124 nanograms per millilitre (ng/mL) | Geometric Coefficient of Variation 50.3 |
90% CI: [8.25, 10.53]
Secondary
Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC]
The relative bioavailability of the TPGS capsules variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | 3750 ng*h/mL | Geometric Coefficient of Variation 24.1 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC] | 975 ng*h/mL | Geometric Coefficient of Variation 31.7 |
90% CI: [24.44, 28.09]
Secondary
Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)]
The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC\[0-t\] of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | 3670 ng*h/mL | Geometric Coefficient of Variation 24 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)] | 866 ng*h/mL | Geometric Coefficient of Variation 31.4 |
90% CI: [22.02, 25.3]
Secondary
Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax]
The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the Cmax of selumetinib in healthy volunteers.
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | 1330 ng/mL | Geometric Coefficient of Variation 36.6 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax] | 172 ng/mL | Geometric Coefficient of Variation 46.5 |
90% CI: [11.42, 14.65]
Secondary
The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t)
The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the AUC(0-t) of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C).
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t) | 267 ng*h/mL | Geometric Coefficient of Variation 31.1 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t) | 30.2 ng*h/mL | Geometric Coefficient of Variation 72.1 |
| Treatment C: Selumetinib Blue TPGS Variant Capsules | The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t) | 33.9 ng*h/mL | Geometric Coefficient of Variation 66.2 |
90% CI: [9.8, 13.05]
90% CI: [11.07, 14.8]
Secondary
The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax
The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the Cmax of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C).
Time frame: Blood samples were collected pre-dose, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose for each of the separate treatment periods (Visits 2, 3 and 4).
Population: The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Selumetinib Blue Reference Capsules | The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax | 95.2 ng/mL | Geometric Coefficient of Variation 34.8 |
| Treatment B: Selumetinib Blue Free Base Variant Capsules | The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax | 9.13 ng/mL | Geometric Coefficient of Variation 50.9 |
| Treatment C: Selumetinib Blue TPGS Variant Capsules | The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax | 12.3 ng/mL | Geometric Coefficient of Variation 48.6 |
90% CI: [8.5, 10.97]
90% CI: [11.45, 14.86]