To Assess the Pharmacokinetics, Safety and Tolerability of Selumetinib in Renal Impaired Subjects and Healthy Subjects

Study Overview
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Brief Summary
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A study to assess the pharmacokinetics, safety and tolerability of Selumetinib (AZD6244, ARRY-142886) in subjects with renal impairment and healthy subjects

Detailed Description
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An open label study to assess the pharmacokinetics, safety and tolerability of 50 mg single oral dose of Selumetinib (AZD6244, ARRY-142886) in subjects with renal impairment and healthy subjects

Official Title
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An Open Label Comparative Study of the Pharmacokinetics, Safety and Tolerability of Selumetinib (AZD6244, ARRY 142886) (Hyd Sulfate) Following a Single Oral Dose in Subjects With Renal Impairment and Healthy Subjects

Conditions
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Solid Tumours

Intervention / Treatment
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* Drug: selumetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria all participants: Male and female (non childbearing potential) subjects aged 18 years or more with suitable veins for cannulation or repeated venipuncture. Have a weight of at least 50 kg (110 lbs) and body mass index (BMI) between 18 and 40 kg/m2, inclusive. Inclusion healthy volunteers only: Must be in good health as determined by a medical history, physical examination, 12 lead ECG, clinical laboratory evaluations, and an ophthalmic examination performed before the administration of the investigational product. Inclusion renal impaired patients only: Stable renal function Exclusion Criteria all participants: Subjects of Japanese or non Japanese Asian ethnicity. Any one parent or grandparent (maternal or paternal) is Japanese or non-Japanese Asian (e.g. China, Taiwan, Korea, Philippines, Thailand, Vietnam and Malaysia). Asian Indians are acceptable. Subjects who smoke more than 10 cigarettes or the equivalent in tobacco per day In the opinion of the investigator, any evidence of additional severe or uncontrolled systemic disease (eg, currently unstable or uncompensated hepatic, cardiovascular, or respiratory disease) or laboratory finding, physical examination, hematology, clinical chemistry, urinalysis, vital signs, or 12-lead ECG that makes it undesirable for the subject to participate in the study. Exclusion renal impaired patients only: Subjects with an active renal transplant (subjects who have previously received a renal transplant and are currently undergoing dialysis due to transplant failure may be enrolled). Acute coronary syndrome within 6 months prior to administration of the investigational product.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HV selumetinib Stage 1<br>Healthy volunteer (HV)group to receive selumetinib 50mg (2x25mg) orally | Drug: selumetinib<br>* selumetinib 50 mg (2x25mg) administered by mouth as capsules<br>|
| Experimental: ESRD selumetinib Stage 1<br>End stage renal disease (ESRD)patients to recieve selumetinib 50mg (2x25mg) orally | Drug: selumetinib<br>* selumetinib 50 mg (2x25mg) administered by mouth as capsules<br>|
| Experimental: Selumetinib stage 2<br>If deemed necessary patients with mild and/or moderate and/or severe renal impairment will recieve selumetinib 50mg(2x25mg) orally | Drug: selumetinib<br>* selumetinib 50 mg (2x25mg) administered by mouth as capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of the pharmacokinetic(PK) profile in terms of maximum observed plasma concentration (Cmax) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of area under plasma concentration-time curve from zero extrapolated to infinity (AUC) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of area under plasma concentration-time curve to time of last measurable concentration (AUC[0-t]) for selumetinib if AUC is not reportable in more than 80% of subjects | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of the safety profile in terms of adverse events, physical examinations, ophthalmologic assessments, vital signs, clinical laboratory assessments and 12-lead electrocardiograms. |  | From screening until follow up. Approximately 6 weeks for healthy volunteers and 8 weeks for renal patients | 
| Description of the PK profile in terms of time to reach maximum observed concentration administration (tmax) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of area under the plasma concentration time curve from zero to 12 hours postdose (AUC[0-12]) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h, and12h | 
| Description of PK profile in terms of terminal rate constant (λz), terminal elimination half-life (t1/2), apparent oral clearance (CL/F) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of apparent volume of distribution at steady state (Vss/F) and apparent volume of distribution during the terminal phase (Vz/F) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of mean residence time (MRT) and fraction unbound (fu), free Cmax (Cmax, u), free AUC (AUCu), free AUC(0-t) (AUC[0-t],u) and unbound CL/F (CL/Fu) | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of PK profile in terms of the amount of drug excreted in urine (Ae) the fraction of dose excreted in urine (fe), renal clearance (CLR) for selumetinib and AUC, Cmax, tmax, t1/2, λz, AUC(0-12) and AUC(0-t) | These collection will be taken on visit 2 for the healthy volunteers and on visit 2 and 3 if the patients can produce urine | The urine collection intervals will be from -12 to 0 (predose), and 0 to 6, 6 to 12, 12 to 24, 24 to 36, 36 to | 
| Description of the PK profile in terms of the metabolite to parent AUC and Cmax ratios (MRAUC and MRCmax) | These samples will be taken on visit 2 for the healthy volunteers and on both visit 2 and visit 3 | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of the PK profile in terms of Ae, fe, and CLR for N-desmethyl selumetinib (and the amide metabolite, if deemed appropriate) |  | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h,12h,18h,24h,36h,48h and 76h | 
| Description of the PK profile in terms of time-matched area under the plasma concentration time curve from 1 to 5 hours postdose (AUC[1-5]) | This will only be taken at the visit when dose is given 1h before dialyse start | Sample taken predose, at 1h just before dialyse and at 5h after the end of the dialyse | 
| Description of the PK profile in terms of cumulative amount extracted during dialysis (Ad[1-5]), and dialysis clearance (CLD) | This will only be collected during visit 2 and only on end stage renal disease patients | Samples taken from dialysate collections over 1 hour intervals throughout the entire (approximately 4 hours) dialysis period ie, 0 to 1, 1 to 2, 2 to 3, 3 | 

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