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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
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| selumetinib 75mg. | Experimental | Volunteers will receive selumetinib 75mg administered by mouth, as a capsule |
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| rifampicin 600mg. | Other | Volunteers will receive rifampicin 600mg administered by mouth, as a capsule |
|
| selumetinib 75mg and rifampicin 600mg | Experimental | Volunteers will receive selumetinib 75mg and rifampicin 600mg, by mouth, as a capsule |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| selumetinib | Drug | Volunteers will receive a single oral dose of 75 mg selumetinib on day 1 (Treatment A). |
|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Safety variables (adverse events, physical examinations, ophthalmologic assessments, vital signs, clinical laboratory assessments, and 12 lead electrocardiograms) | Assessments performed during each of the 3 treatments | Baseline (Day-1) up to Day 25 |
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.
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| Name | Affiliation | Role |
|---|---|---|
| Eleanor Lisbon, 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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| ID | Term |
|---|---|
| C517975 | AZD 6244 |
| D012293 | Rifampin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| rifampicin | Drug | Volunteers will receive single, daily, oral doses of 600 mg rifampicin on Days 4 to 11 (Treatment B). |
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| selumetinib | Drug | On day 12 volunteers will receive a single oral dose of 75 mg selumetinib (Treatment C). |
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| rifampicin | Drug | 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). |
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| 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 |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |