A Study to Assess the Relative Bioavailability of Process Variants of Selumetinib in Healthy Male Volunteers

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Single Centre, Randomised, Open Label, Crossover Study to Assess the Bioequivalence or Relative Bioavailability of Variants of Selumetinib (AZD6244, Hyd-Sulfate) Blue Capsules in Healthy Male Volunteers Aged 18 to 45 Years

Conditions
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Healthy Volunteers Bioequivalence or Bioavailability Study

Intervention / Treatment
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* Drug: selumetinib 75mg single dose
* Drug: selumetinib 75mg single dose
* Drug: selumetinib 75mg single dose


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>AZD6244 blue reference capsules (3 x 25 mg) administered orally | Drug: selumetinib 75mg single dose<br>* 3 blue capsules of 25 mg given as a single dose<br>* Other names: Selumetinib;|
| Experimental: Treatment B<br>AZD6244 blue capsules (3 x 25 mg) Variant 1 (free base variant) administered orally | Drug: selumetinib 75mg single dose<br>* 3 capsules of 25 mg given as a single dose<br>* Other names: Selumetinib;|
| Experimental: Treatment C<br>AZD6244 blue capsules (3 x 25 mg) Variant 2 (vitamin E polyethylene glycol succinate [TPGS] variant) administered orally | Drug: selumetinib 75mg single dose<br>* 3 capsules of 25 mg given as a single dose<br>* Other names: Selumetinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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 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). | 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 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). | 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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bioequivalence, bioavailability, pharmacokinetics, Phase I, AZD6244, cancer