Absorption and Elimination of Radiolabeled Daprodustat

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Anaemia

Treatments: Drug: [14C]-GSK1278863 solution for IV infusion; Drug: Daprodustat 6 mg oral tablet; Drug: [14C]-GSK1278863 oral solution

Study type: Interventional

Funder types: Industry

Identifiers

NCT03239522

2017-001729-42 (EudraCT Number)

200232

Details and patient eligibility

About

Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied in previous clinical trials; however, the elimination routes and metabolic pathways of daprodustat have not been fully elucidated in humans. This is an open-label, single-center, non-randomized, 2-period, single-sequence, crossover, mass balance study in 6 healthy male participants. The aim of the study is to assess the excretion balance of daprodustat using [14C]-radiolabeled drug substance administered orally, and as an intravenous (IV) infusion, administered as a microtracer dose (concomitant with an oral, non-radiolabeled dose). Absolute bioavailability of an oral dose will also be assessed. Each participant will be involved in the study for up to 10 weeks which include a screening visit, two treatment periods (treatment periods 1 and 2), separated by about 7 days (at least 14 days between oral doses), and a follow up visit 1-2 weeks after the last assessment in treatment period 2. The primary objective of the study is to gain a better understanding of the compound's excretory and metabolic profile. This study will include sampling of duodenal bile to conduct qualitative assessment of drug metabolites in this matrix in order to characterize biliary elimination pathways.

Enrollment: 6 patients

Sex: Male

Ages: 30 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Aged 30 to 55 years, inclusive, at the time of signing the informed consent.
• Healthy, as determined by the investigator or medically qualified designee, based on a medical evaluation including medical history, physical examination, vital signs, laboratory tests, and ECG. A participant with a clinical abnormality or laboratory parameter (i.e., outside the reference range for the population being studied), which is not specifically listed in the eligibility criteria, may be included only if the investigator agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Hemoglobin value at screening greater than the lower limit of the laboratory reference range and less than or equal to 16.0 gram (g) per deciliter (dL).
• History of regular bowel movements (averaging one or more bowel movements per day).
• Non-smoker, or ex-smoker who hasn't regularly smoked for the 6 months before screening.
• Body weight of 50 kilogram (kg) and above, and body mass index (BMI) within the range 19.0-31 kg per meter (m)^2 (inclusive).
• Participants must agree to use contraception as follows: participants with female partners of childbearing potential must agree to use a condom from the time of first dose of study treatment until 1 month after their last dose.
• Capable of giving signed informed consent.
• Willingness to give written consent to have data entered into The Over-volunteering Prevention System.

Exclusion criteria

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Participants with a history of cholecystectomy must be excluded.
• Any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or 12-lead ECG.
• Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening through to enrollment (Day 1, treatment period 1).
• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs, or which could constitute a risk when taking the study treatment, or interfere with the interpretation of data.
• Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant GI bleeding <=12 weeks prior to screening through to enrollment (Day 1, treatment period 1).
• History of malignancy within the two years before dosing, with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to screening; currently receiving treatment for cancer; has a strong family history of cancer (e.g., familial cancer disorders).
• Mentally or legally incapacitated.
• Heart Failure: Class II, III or IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
• Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
• Daprodustat is a substrate of cytochrome P4502C8 (CYP2C8). Co-administration of drugs that are inhibitors of this enzyme are prohibited.
• Past or intended use of over-the-counter or prescription medication including herbal medications prior to dosing except occasional use of paracetamol (acetaminophen), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study treatment until completion of the follow-up visit, unless in the opinion of the investigator and GSK medical monitor the medication will not interfere with the study.
• Current enrolment in a clinical trial; recent participation in a clinical trial and has received an investigational product within 3 months before their first dose in the current study.
• Exposure to more than 4 new chemical entities within 12 months before their first dose in the current study.
• Participation in a clinical trial involving administration of 14C-labelled compound(s) within the last 12 months. A participant's previous effective dose will be reviewed by the medical investigator to ensure there is no risk of contamination/carryover into the current study.
• Received a total body radiation dose of greater than 10.0 millisievert (mSv) (upper limit of world health organization [WHO] category II) or exposure to significant radiation (e.g., serial x-ray or computed tomography [CT] scans, barium meal, etc.) in the 3 years before this study.
• Alanine transaminase (ALT) >1.5 times upper limit of normal (ULN).
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• QTc >500 millisecond (msec). The QTc must be the QTcB.
• Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening or within 3 months before the first dose of study treatment.
• Positive pre-study drug/alcohol screen.
• Positive human immunodeficiency virus (HIV) antibody test.
• Regular use of known drugs of abuse.
• Regular alcohol consumption within 6 months prior to the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a glass (approximately 240 milliliter [mL]) of beer, 1 small glass (approximately 100 mL) of wine or 1 (approximately 25 mL) measure of spirits.
• At screening, a supine blood pressure (BP) that is persistently higher than 140/90 millimeters of mercury (mmHg) taken in triplicate, unless deemed not clinically significant by the investigator.
• At screening, a supine mean heart rate (HR) outside the range of 40-100 beats per minute, unless deemed not clinically significant by the investigator.
• Has had an occupation which requires monitoring for radiation exposure, nuclear medicine procedures, or excessive x-rays within the past 12 months.
• Unable to refrain from consumption of prohibited food and drinks from 7 days before the first dose of study medication until the follow up visit.
• Participation in the study would result in donation of blood or blood products in excess of 550 mL within a 90 day period.
• Unwillingness or inability to follow the procedures, including the use of the Entero-Test capsule.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products in the 6 months prior to screening.
• History of drug abuse or dependence within 6 months of the study.
• History of sensitivity to daprodustat, or their components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GSK medical monitor, contraindicates their participation.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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6 participants in 1 patient group

All participants receiving treatment

Experimental group

Description:

Each participant will receive a single 6 milligram (mg) oral dose of daprodustat on Day 1 of period 1. After approximately 1 hour, participants will receive 50 microgram (µg) of \[14C\]-GSK1278863 by IV infusion over 1 hour. On Day 1 of period 2, each participant will receive 25 mg \[14C\]-GSK1278863 as an oral solution.

Treatment:

Drug: [14C]-GSK1278863 oral solution

Drug: Daprodustat 6 mg oral tablet

Drug: [14C]-GSK1278863 solution for IV infusion