Healthy Volunteers Bioequivalence or Bioavailability Study Clinical Trial
Official title:
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
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.
| Status | Completed |
| Enrollment | 48 |
| Est. completion date | April 2015 |
| Est. primary completion date | April 2015 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | Male |
| Age group | 18 Years to 45 Years |
| Eligibility |
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 |
Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Research Site | London |
| Lead Sponsor | Collaborator |
|---|---|
| AstraZeneca |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Bioequivalence of the free base variant of selumetinib (Treatment B) compared to the blue reference capsule (Treatment A) | Selumetinib bioequivalent will be evaluated by comparing the following parameters: maximum observed plasma concentration (Cmax) and area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) or area under the plasma concentration time curve from time zero to the time of last quantifiable concentration [AUC(0-t)] | Blood samples are 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 - samples taken at each of the 3 treatment periods | No |
| Secondary | Relative bioavailability of the TPGS (Vitamin E polyethylene glycol succinate) capsule variant of selumetinib (Treatment C) compared to the blue reference capsule (Treatment A) in terms of Selumetinib Cmax and AUC or AUC(0-t) | Blood samples are 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 - samples taken at each of the 3 treatment periods | No | |
| Secondary | PK (Pharmacokinetics) of selumetinib by assessment of time to reach maximum observed concentration administration (tmax). | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of area under the plasma concentration time curve from time zero to 12 hours postdose [AUC(0 12)] | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of area under the plasma concentration time curve from time zero to the time of last quantifiable concentrationAUC(0-t) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of terminal rate constant (?z) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of terminal half-life (t1/2) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of apparent systemic clearance (CL/F) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of apparent volume of distribution at steady state (Vss/F) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of apparent volume of distribution during the terminal phase (Vz/F) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of selumetinib by assessment of mean residence time (MRT) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of Cmax | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of AUC | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of tmax | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of AUC(0 12) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of AUC(0-t) | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of ?z | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of t1/2 | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of the metabolite to parent AUC | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | PK of N desmethyl selumetinib by assessment of Cmax ratios [MRAUC (Ratio of metabolite to parent AUC) and MRCmax (Ratio of metabolite to parent Cmax) respectively] | Blood samples are 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 - samples taken at each of the 3 treatment periods. | No | |
| Secondary | Safety and tolerability of selumetinib | Number, severity and related causality of adverse events, clinically significant change from baseline in the physical examination, ophthalmology assessments, vital signs, clinical laboratory assessments, 12-Lead electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) | from screening visit up to 65 days | Yes |