To Assess the Effect of Rifampicin 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 Rifampicin on the pharmacokinetics of Selumetinib (AZD6244; ARRY-142886) (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 inducer Rifampicin on the Pharmacokinetics of a 75 mg Single Oral Dose of Selumetinib (AZD6244; ARRY-142886) (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 Inducer Rifampicin on the Pharmacokinetics of a 75 mg Single Oral Dose of Selumetinib (AZD6244; ARRY-142886) (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: rifampicin
* Drug: selumetinib
* Drug: rifampicin


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 (inclusive). 2. Must not have smoked or used nicotine products within the previous 3 months. 3. Have a calculated creatinine clearance (CrCL) greater than 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 (eg, 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 greater than 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. 5. History of presence of any clinically significant disease or disorder 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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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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: selumetinib 75mg.<br>Volunteers will receive selumetinib 75mg administered by mouth, as a capsule | Drug: selumetinib<br>* Volunteers will receive a single oral dose of 75 mg selumetinib on day 1 (Treatment A).<br>* Other names: AZD6244;|
| Other: rifampicin 600mg.<br>Volunteers will receive rifampicin 600mg administered by mouth, as a capsule | Drug: rifampicin<br>* Volunteers will receive single, daily, oral doses of 600 mg rifampicin on Days 4 to 11 (Treatment B).<br>* Other names: AZD6244;|
| Experimental: selumetinib 75mg and rifampicin 600mg<br>Volunteers will receive selumetinib 75mg and rifampicin 600mg, by mouth, as a capsule | Drug: selumetinib<br>* On day 12 volunteers will receive a single oral dose of 75 mg selumetinib (Treatment C).<br>Drug: rifampicin<br>* On day 12 volunteers will receive a single oral dose of 600 mg rifampicin. Once daily rifampicin administrations will continue through to Day 14 (Treatment C).<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment 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 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment 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 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment of maximum plasma concentration (Cmax) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment of time to Cmax (tmax) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, by assessment of apparent systemic plasma clearance (CL/F) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, by assessment of apparent volume at distribution equilibrium, mean residence time (MRT)*CL/F (Vss/F) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, by assessment of apparent volume at distribution (Vz/F) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment of terminal half-life (t1/2) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib, N-desmethyl selumetinib,(and the amide metabolite, if deemed appropriate) by assessment of terminal rate constant (λz) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assessment of AUC metabolite to parent ratio, n-desmethyl selumetinib (MRAUC) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib and N-desmethyl selumetinib by assessment of Cmax metabolite to parent ratio, n-desmethyl selumetinib (MRCmax) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post dose | 
| Pharmacokinetics of selumetinib by assessment of mean residence time (MRT) | Samples taken during each of the 3 treatments | Blood samples are collected pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 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,