Solid Tumours
Conditions
Keywords
Phase I, healthy, pharmacokinetics, renal impairment
Brief summary
A study to assess the pharmacokinetics, safety and tolerability of Selumetinib (AZD6244, ARRY-142886) in subjects with renal impairment and healthy subjects
Detailed description
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
Interventions
DRUGselumetinib
selumetinib 50 mg (2x25mg) administered by mouth as capsules
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
all participants: 1. Male and female (non childbearing potential) subjects aged 18 years or more with suitable veins for cannulation or repeated venipuncture. 2. 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: 3. 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: 4. Stable renal function
Exclusion criteria
all participants: 1. Subjects of Japanese or non Japanese Asian ethnicity. 2. 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. 3. Subjects who smoke more than 10 cigarettes or the equivalent in tobacco per day 4. 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: 5. 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). 6. Acute coronary syndrome within 6 months prior to administration of the investigational product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Description of the pharmacokinetic(PK) profile in terms of maximum observed plasma concentration (Cmax) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| Description of PK profile in terms of area under plasma concentration-time curve from zero extrapolated to infinity (AUC) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| 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 | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Description of PK profile in terms of terminal rate constant (λz), terminal elimination half-life (t1/2), apparent oral clearance (CL/F) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| 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) | 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 | These collection will be taken on visit 2 for the healthy volunteers and on visit 2 and 3 if the patients can produce urine |
| 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) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| 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) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| 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 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]) | Sample taken predose, at 1h just before dialyse and at 5h after the end of the dialyse | This will only be taken at the visit when dose is given 1h before dialyse start |
| Description of the PK profile in terms of cumulative amount extracted during dialysis (Ad[1-5]), and dialysis clearance (CLD) | 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 | This will only be collected during visit 2 and only on end stage renal disease patients |
| Description of the PK profile in terms of the metabolite to parent AUC and Cmax ratios (MRAUC and MRCmax) | 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 | These samples will be taken on visit 2 for the healthy volunteers and on both visit 2 and visit 3 |
| Description of the PK profile in terms of time to reach maximum observed concentration administration (tmax) | 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 | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
| Description of PK profile in terms of area under the plasma concentration time curve from zero to 12 hours postdose (AUC[0-12]) | Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h, and12h | This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease |
Countries
United States
Outcome results
None listed