To Assess the Effect of Itraconazole and Fluconazole on the Pharmacokinetics of Selumetinib in Healthy Male Volunteers

Study Overview
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Brief Summary
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Study to assess the effect of Itraconazole and Fluconazole on the pharmacokinetics of Selumetinib (AZD6244; ARRY-142866) ( Hyd-Sulfate) in Healthy Male Volunteers

Detailed Description
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A Open-label, Single-center Study to Assess the Effect of the CYP3A4 Inhibitor Itraconazole and the CYP2C19 Inhibitor Fluconazole on the Pharmacokinetics of a 25 mg Single Oral Dose of Selumetinib (AZD6244; ARRY-142866) ( Hyd-Sulfate) in Healthy Volunteers

Official Title
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A Phase I, Open-label, Single-center Study to Assess the Effect of the CYP3A4 Inhibitor Itraconazole and the CYP2C19 Inhibitor Fluconazole on the Pharmacokinetics of a 25 mg Single Oral Dose of Selumetinib (AZD6244; ARRY-142866) ( Hyd-Sulfate) in Healthy Volunteers Aged 18 to 45 Years

Conditions
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Solid Tumours

Intervention / Treatment
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* Drug: selumetinib
* Drug: itraconazole
* Drug: itraconazole
* Drug: selumetinib
* Drug: selumetinib
* Drug: fluconazole
* Drug: fluconazole
* Drug: selumetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Have a body mass index (BMI) between 18 and 30 kg/m2 (inclusive) and weigh at least 50 kg and no more than 100 kg. 2. Female subjects of non-childbearing potential. 3. Have a calculated creatinine clearance (CrCL) >50 mL/min using the Cockcroft-Gault formula. Exclusion Criteria: 1. Subjects of Japanese or non-Japanese Asian ethnicity. 2. Any one parent or grandparent (maternal or paternal) is Japanese or non-Japanese. Asian (ie, China, Taiwan, Korea, Philippines, Thailand, Vietnam and Malaysia). Asian Indians are acceptable. 3. Current or past history of central serous retinopathy or retinal vein thrombosis,intra-ocular pressure >21 mmHg or uncontrolled glaucoma. 4. Any clinically relevant abnormal findings in physical examination, hematology, clinical chemistry, urinalysis, vital signs or ECG at baseline in the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: selumetinib; itraconazole; selumetinib + itraconazole<br>Volunteers will receive selumetinib 25mg alone; itraconazole 200mg pre-dosing; selumetinib 25mg and itraconazole 200mg; all adminstered by mouth as a capsule | Drug: selumetinib<br>* Volunteers will recieve single oral dose of 25mg selumetinib in sequence 1, treatment A<br>* Other names: (AZD6244; ARRY-142866) ( Hyd-Sulfate);Drug: itraconazole<br>* Volunteers will receive oral doses of itraconazole 200 mg twice daily on Day 1 to Day 7 in sequence 1 treatment B:<br>Drug: itraconazole<br>* Volunteers will recieve a single morning dose of 200mg itraconazole on Day 8 and twice daily doses of 200mg itraconazole on Day 8 to Day 11; sequence 1 treatment C.<br>Drug: selumetinib<br>* Volunteers willl recieve a single oral dose of 25 mg selumetinib (4 hours fasted state) on Day 8; sequence 1 treatment C.<br>* Other names: (AZD6244; ARRY-142866) ( Hyd-Sulfate);|
| Experimental: selumetinib; fluconazole; selumetinib + fluconazole<br>Volunteers will receive selumetinib 25mg alone administered by mouth as a capsule; fluconazole 400mg and fluconazole 200mg pre-dosing, administered by mouth as a tablet; selumetinib 25mg and fluconazole 200mg. | Drug: selumetinib<br>* Volunteers will recieve single oral dose of 25mg selumetinib in sequence 2, treatment A.<br>* Other names: (AZD6244; ARRY-142866) ( Hyd-Sulfate);Drug: fluconazole<br>* Volunteers will recieve a single dose of 400 mg fluconazole on Day 1 and daily doses of 200 mg fluconazole on Day 2 to Day 7; sequence 2 treatment D.<br>Drug: fluconazole<br>* Volunteers will receive a morning dose of 200mg fluconazole on Day 8 and daily doses of 200mg fluconazole on Day 8 to Day 11; sequence 2 treatment E<br>Drug: selumetinib<br>* Volunteers will receive a single dose of 25mg selumetinib (4 hours fasted state) on Day 8; sequence 2 treatment E<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assessment of area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of area under the plasma concentration-time from time zero to the time of the last quantifiable concentration (AUC(0-t) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of area under the plasma concentration-time curve from time zero to 12 hours post-dose AUC(0-12) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of maximum plasma concentration (Cmax) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of time to Cmax (tmax) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib by assesement of apparent oral plasma clearance (CL/F) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib by assesement of apparent volume at distribution steady state, (MRT)*CL/F (Vss/F) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib by assesement of apparent volume at distribution (Vz/F) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of terminal half-life (t1/2) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of terminal rate constant (λz) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of AUC metabolite to parent ratio (MRAUC) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assesement of Cmax metabolite to parent ratio (MRCmax) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 
| Pharmacokinetics of selumetinib by assesement of mean residence time (MRT) | Samples taken during each of the 6 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, healthy, pharmacokinetics