Clinical trial NCT02063204: To Assess the Pharmacokinetics, Safety and Tolerability of Selumetinib in Renal Impaired Subjects and Healthy Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: Phase I, healthy, pharmacokinetics, renal impairment
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-02-14
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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.

Primary outcomes:
measure: Description of the pharmacokinetic(PK) profile in terms of maximum observed plasma concentration (Cmax)
timeFrame: 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
measure: Description of PK profile in terms of area under plasma concentration-time curve from zero extrapolated to infinity (AUC)
timeFrame: 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
measure: 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
timeFrame: 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 outcomes:
measure: Description of the safety profile in terms of adverse events, physical examinations, ophthalmologic assessments, vital signs, clinical laboratory assessments and 12-lead electrocardiograms.
timeFrame: From screening until follow up. Approximately 6 weeks for healthy volunteers and 8 weeks for renal patients
measure: Description of the PK profile in terms of time to reach maximum observed concentration administration (tmax)
timeFrame: 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
measure: Description of PK profile in terms of area under the plasma concentration time curve from zero to 12 hours postdose (AUC[0-12])
timeFrame: Samples taken at predose, 30min, 1h, 1h30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 5h,6h,7h,8h, and12h
measure: Description of PK profile in terms of terminal rate constant (λz), terminal elimination half-life (t1/2), apparent oral clearance (CL/F)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Description of the PK profile in terms of the metabolite to parent AUC and Cmax ratios (MRAUC and MRCmax)
timeFrame: 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
measure: Description of the PK profile in terms of Ae, fe, and CLR for N-desmethyl selumetinib (and the amide metabolite, if deemed appropriate)
timeFrame: 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
measure: 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])
timeFrame: Sample taken predose, at 1h just before dialyse and at 5h after the end of the dialyse
measure: Description of the PK profile in terms of cumulative amount extracted during dialysis (Ad[1-5]), and dialysis clearance (CLD)
timeFrame: 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
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Research Site
state: Florida
Study officials:
affiliation: Orlando Clinical Research Centre, US
name: Thomas C Marbury, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Astrazeneca United kingdom
name: Ian Smith, MD
role: STUDY_DIRECTOR
References: