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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
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| selumetinib; itraconazole; selumetinib + itraconazole | Experimental | Volunteers will receive selumetinib 25mg alone; itraconazole 200mg pre-dosing; selumetinib 25mg and itraconazole 200mg; all adminstered by mouth as a capsule |
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| selumetinib; fluconazole; selumetinib + fluconazole | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| selumetinib | Drug | Volunteers will recieve single oral dose of 25mg selumetinib in sequence 1, treatment A |
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| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Safety variables (adverse events, physical examinations, opthalmologic assessements, vital signs, clinical laboratory assessments and 12 lead electrocardiograms) | Assessments performed during each of the 6 treatments | Baseline (Day-1) up to Day 24 |
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.
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| Name | Affiliation | Role |
|---|---|---|
| David R Mathews, MD | Quintiles 6700 W 115th Street, Kansas, US | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Overland Park | Kansas | United States |
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| Label | URL |
|---|---|
| CSR\_Synopsis\_D1532C00083 | View source |
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| itraconazole | Drug | Volunteers will receive oral doses of itraconazole 200 mg twice daily on Day 1 to Day 7 in sequence 1 treatment B: |
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| itraconazole | Drug | 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. |
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| selumetinib | Drug | Volunteers willl recieve a single oral dose of 25 mg selumetinib (4 hours fasted state) on Day 8; sequence 1 treatment C. |
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| selumetinib | Drug | Volunteers will recieve single oral dose of 25mg selumetinib in sequence 2, treatment A. |
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| fluconazole | Drug | 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. |
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| fluconazole | Drug | 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 |
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| selumetinib | Drug | Volunteers will receive a single dose of 25mg selumetinib (4 hours fasted state) on Day 8; sequence 2 treatment E |
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| 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 |
| ID | Term |
|---|---|
| C517975 | AZD 6244 |
| D017964 | Itraconazole |
| D015725 | Fluconazole |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D010879 | Piperazines |
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