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To assess the absolute bioavailability of a single oral dose of AZD9291 with respect to an intravenous microdose of \[14C\]AZD9291

Single oral dose of 80 mg AZD9291 tablet on Day 1 administered orally with 240 mL water following an overnight fast.

AZD9291

Each healthy male subject will also receive a single, radiolabeled, 100 μg dose of \[14C\] AZD9291 administered as an IV microdose infusion starting at 5 hours and 45 minutes after receiving the oral dose.

[14C]AZD9291

Joanne Collier, MBChB, FFPM, Dip Stats (OU)

The Sponsor is developing the study drug, AZD9291, for the potential treatment of nonsmall cell lung cancer. Lung cancer has been the most common cancer in the world for several decades and represents 12.8% of all new cancer cases in 2008.

The purpose of this study is to see how much AZD9291 is taken up by the body when dosed by mouth (tablet) compared to when the study drug is dosed once by injection directly into the vein (intravenously). The dose given directly into the vein will be radiolabelled. This means that the test drug has a radioactive component which helps us to track where the drug is in the body. This allows us to detect the differences between the tablet and the intravenous dose.

The study will be performed in 12 healthy male subjects aged 18-65 years. On Day 1, subjects will be dosed with a single oral dose of 80 milligrams AZD9291 tablet followed by 100 micrograms \[14C\] AZD9291 dosed as an intravenous microdose beginning 5 hours and 45 minutes after the oral dose has been administered. Subjects will remain in the study centre until after the 120 hour post-dose blood sample is obtained and will return to the clinic for further visits on Day 8, 10, 15 and 22 for pharmacokinetic and safety assessments.

The study is a Phase I, open label, single dose, single centre study performed in 12 healthy male subjects aged 18 to 65 years, inclusive. This study will assess the absolute bioavailability of AZD9291 and evaluate the PK parameters following a single oral dose of AZD9291 and a radiolabelled IV microdose of AZD9291 in healthy male subjects. Oral AZD9291and \[14C\] AZD9291 intravenous solution are referred to as the investigational products in this study.

A screening visit (Visit 1) to assess the eligibility of the healthy male subjects will occur within 28 days of the administration of the investigational product. Screening assessments will include evaluation of opthalmological assessments, clinical chemistry, haematology, urinalysis, a physical examination, vital signs, 12-lead electrocardiograms (ECGs), medical and surgical history, screening for drugs of abuse, alcohol, hepatitis B and C, and HIV, and recording of concomitant medications and Adverse Events. Study related procedures will only be performed after signing of the Informed Consent Form.

The healthy male subjects will be admitted to the study centre the day before administration of the investigational product (Day 1; Visit 2). On Day 1 (Visit 2), subjects will be dosed with a single oral dose of 80 mg AZD9291 tablet followed by 100 μg \[14C\] AZD9291 dosed as an IV microdose beginning 5 hours and 45 minutes after the oral dose has been administered. The IV microdose will be infused over 15 minutes and the end of the infusion will be co incidental with median oral tmax (ie, estimated tmax is 6 hours).

The subjects will remain in the study centre until the 120 hour post dose PK blood sample is obtained. Ambulatory visits will occur on Days 8 (Visit 3), 10 (Visit 4), 15 (Visit 5) and 22 (Visit 6) for PK and safety assessments. A follow up visit (Visit 7) will occur 21 to 28 days after discharge (Days 27 - 34) from the study centre and will include routine safety assessments.

A Phase I, Open-label Study to Assess Bioavailability of a Single Oral Dose of AZD9291 vs an IV Dose of [14C]AZD9291

A Phase I, Open-label, Single Dose, Single-Centre Study to Assess the Absolute Bioavailability of a Single Oral Dose of AZD9291 With Respect to an Intravenous Microdose of [14C]AZD9291 in Healthy Male Subjects

Absolute bioavailability of AZD9291 will be calculated from area under the plasma concentration versus time curve (AUC) of the oral dose of AZD9291 / AUC of the IV dose of \[14C\]AZD9291 x IV dose/Oral dose x 100

Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from zero to infinity for AZD9291 and it's metabolites AZ5104 and AZ7550.

Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 24 hours (AUC 0-24) for AZD9291 and it's metabolites AZ5104 and AZ7550.

Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 120 hours (AUC 0-120) for AZD9291 and it's metabolites AZ5104 and AZ7550.

Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to the last quantifiable concentration (AUC 0-t) for AZD9291 and it's metabolites AZ5104 and AZ7550.

PK profile of the oral dose of AZD9291 in terms of the maximum observed plasma concentration (Cmax) for AZD9291 and it's metabolites AZ5104 and AZ7550.

PK profile of the oral dose of AZD9291 in terms of the time to maximum observed plasma concentration (Tmax) for AZD9291 and it's metabolites AZ5104 and AZ7550.

PK profile of the oral dose of AZD9291 in terms of the elimination half life (t1/2,λz) for AZD9291 and it's metabolites AZ5104 and AZ7550.

PK profile of the oral dose of AZD9291 in terms of apparent total body clearance of drug from plasma after extravascular administration(CL/F) for AZD9291.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from zero to infinity for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 24 hours (AUC 0-24) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 120 hours (AUC 0-120) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to the last quantifiable concentration (AUC 0-t) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the maximum observed plasma concentration (Cmax) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the the time to maximum observed plasma concentration (Tmax) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the elimination half life (t1/2,λz) for \[14C\]AZD9291 and it's metabolites \[14C\]AZ5104 and \[14C\]AZ7550.

Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of total body clearance of drug from plasma after intravascular administration (CL) for \[14C\]AZD9291.

AstraZeneca

Regular investigator assessment at study visits.

Single oral dose of 80 mg AZD9291 tablet on Day 1 and a single, radiolabeled, 100 μg dose of \[14C\] AZD9291 administered as an IV microdose infusion starting at 5 hours and 45 minutes after receiving the oral dose.

AZD9291 and [14C]AZD9291

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Dr Karen So

PK analysis set included all healthy male subjects who received at least 1 dose of AZD9291 and have at least 1 post-dose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of AZD9291.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I, Open-label Study to Assess Bioavailability of a Single Oral Dose of AZD9291 vs an IV Dose of [14C]AZD9291	NCT02491944	Oncology	AZD9291 [14C]AZD9291	18 Years - 65 Years	AstraZeneca
A Phase I, Open-label Study to Assess Bioavailability of a Single Oral Dose of AZD9291 vs an IV Dose of [14C]AZD9291	NCT02491944	Oncology	AZD9291 [14C]AZD9291	18 Years - 65 Years	AstraZeneca

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