Study to Investigate the Absorption, Metabolism, and Excretion of [14C]-GDC-9545 Following a Single Oral Dose (Part 1) and to Evaluate the Absolute and Relative Bioavailability of Oral Capsule Formulations of GDC-9545 (Part 2) in Healthy Female Subjects of Non-Childbearing Potential
Study Details
Study Description
Brief Summary
This is an open-label, single-center, two part study in healthy female subjects of non-childbearing potential to investigate the absorption, metabolism, and excretion of [14C]-GDC-9545 (Part 1), the absolute bioavailability of formulations F12 and F18 (i.e., GDC-9545/F12 capsule, 30 mg and GDC-9545/F18 capsule, 30 mg) and relative bioavailability of GDC-9545 oral capsule F18 to the F12 formulation (Part 2). It is planned that Part 1 will begin prior to Part 2 of the study, and that the two parts of the study will partially overlap.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1: [14C]-GDC-9545 Participants will be enrolled to receive a single dose of Carbon-14 labelled [14C]-GDC-9545. |
Drug: [14C]-GDC-9545
Participants will receive a single oral dose of [14C]-GDC-9545 capsule, 30 milligrams (mg) (not more than 4.6 MBq [124 μCi]) with approximately 240 millilitres (mL) water in the fasted state.
Other Names:
|
| Experimental: Part 2: GDC-9545 Treatment Sequence BCD Participants will be randomly allocated to one of two treatment sequences (BCD for this arm). In each treatment period, participants will receive a single dose of GDC-9545 in the fasted state in each of three treatment periods. The three treatment periods will be separated by a treatment-free washout between each study drug administration. |
Drug: GDC-9545 Solution for Infusion
Treatment B: 30 mg GDC-9545 as a Solution for Infusion, 3 mg/mL administered intravenously in 10 mL as an infusion over 30 minutes.
Other Names:
Drug: GDC-9545/F12 Capsule
Treatment C: GDC-9545/F12 capsule, 30 mg, administered with approximately 240 mL water.
Other Names:
Drug: GDC-9545/F18 Capsule
Treatment D: GDC-9545/F18 capsule, 30 mg, administered with approximately 240 mL water.
Other Names:
|
| Experimental: Part 2: GDC-9545 Treatment Sequence BDC Participants will be randomly allocated to one of two treatment sequences (BDC for this arm). In each treatment period, participants will receive a single dose of GDC-9545 in the fasted state in each of three treatment periods. The three treatment periods will be separated by a treatment-free washout between each study drug administration. |
Drug: GDC-9545 Solution for Infusion
Treatment B: 30 mg GDC-9545 as a Solution for Infusion, 3 mg/mL administered intravenously in 10 mL as an infusion over 30 minutes.
Other Names:
Drug: GDC-9545/F12 Capsule
Treatment C: GDC-9545/F12 capsule, 30 mg, administered with approximately 240 mL water.
Other Names:
Drug: GDC-9545/F18 Capsule
Treatment D: GDC-9545/F18 capsule, 30 mg, administered with approximately 240 mL water.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part 1: Mass Balance Recovery of Cumulative Amount of Total Radioactivity (CumAe) of [14C]-GDC-9545 in All Excreta (Urine and Feces) Overall [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Mass Balance Recovery of Cumulative Amount of Total Radioactivity Expressed as a Percentage of the Radioactive Dose Administered (CumFe) of [14C]-GDC-9545 in All Excreta (Urine and Feces) Overall [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Amount of Total Radioactivity (Ae) of [14C]-GDC-9545 Recovered by Interval for All Excreta (Urine and Feces) [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Cumulative Amount of Total Radioactivity (CumAe) of [14C]-GDC-9545 Recovered by Interval for All Excreta (Urine and Feces) [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Amount of Total Radioactivity Expressed as a Percentage of the Radioactive Dose Administered (Fe) of [14C]-GDC-9545 Recovered by Interval for All Excreta (Urine and Feces) [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Cumulative Amount of Total Radioactivity Expressed as a Percentage of the Radioactive Dose Administered (CumFe) of [14C]-GDC-9545 Recovered by Interval for All Excreta (Urine and Feces) [From Day 1 to Day 21 or until discharge criteria are met (up to 42 days)]
- Part 1: Maximum Observed Concentration (Cmax) of [14C]-GDC-9545, Estimated in Plasma and by Total Radioactivity in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: Time to Maximum Observed Concentration (tmax) of [14C]-GDC-9545, Estimated in Plasma and by Total Radioactivity in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: Area Under the Concentration-Time Curve from Time 0 to the Time of Last Measurable Concentration (AUC0-t) of [14C]-GDC-9545, Estimated in Plasma and by Total Radioactivity in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: Area Under the Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUC0-∞) of [14C]-GDC-9545, Estimated in Plasma and by Total Radioactivity in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: Terminal Elimination Half-Life (t1/2) of [14C]-GDC-9545, Estimated in Plasma and by Total Radioactivity in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: Concentrations of Total Radioactivity of [14C]-GDC-9545 in Plasma and Whole Blood Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 1: The Ratio of Concentrations of Total Radioactivity of [14C]-GDC-9545 in Whole Blood to Plasma Samples [Pre-dose and 1, 1.5, 2, 2.5, 3, 5, 6, 8, and 12 hours post-dose on Day 1, daily from Day 2 to Day 21, and Days 28, 35, and 42]
- Part 2: Absolute Bioavailability (F) of GDC-9545/F12 and F18 Capsules Calculated Based on AUC0-∞, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Relative Bioavailability (Frel AUC0-∞) of GDC-9545/F18 Capsule Compared to GDC-9545/F12 Capsule Calculated Based on AUC0-∞, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Relative Bioavailability (Frel Cmax) of GDC-9545/F18 Capsule Compared to GDC-9545/F12 Capsule Calculated Based on Cmax, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
Secondary Outcome Measures
- Part 2: Cmax of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: tmax of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: AUC0-t of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: AUC0-∞ of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: t1/2 of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: First Order Rate Constant Associated with Terminal Portion of the Curve (λz) of GDC-9545 Solution for Infusion and/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Total Body Clearance (CL) of GDC-9545 Solution for Infusion, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Total Body Clearance Calculated After a Single Extravascular Administration Where Fraction of Dose Bioavailable is Unknown (CL/F) of GDC-9545/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Apparent Volume of Distribution Based on the Terminal Phase Calculated Using AUC0- After a Single IV Administration (Vz) of GDC-9545 Solution for Infusion, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Part 2: Apparent Volume of Distribution (Vz/F) of GDC-9545/F12 and F18 Capsules, Estimated in Plasma Samples [For each treatment period: Pre-dose and 0.25, 0.5, 0.58, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post-dose on Day 1, and daily from Day 2 to Day 8]
- Parts 1 and 2: Number of Participants with Adverse Events, with Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) [From Baseline until end of study (up to 42 days)]
- Parts 1 and 2: Number of Participants with Abnormalities in Laboratory Safety Tests [From Baseline until end of study (up to 42 days)]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy female subjects of non-childbearing potential that are non-pregnant, non-lactating females, who are either postmenopausal or surgically sterile, aged 30 to 65 years, inclusive, at time of signing the Informed Consent Form (ICF)
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A body mass index (BMI) between 18.5 and 32.0 kg/m^2, inclusive, at screening
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Ability to comply with the study protocol
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Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day) (Part 1 only)
Exclusion Criteria:
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Women of childbearing potential, women who are pregnant or breastfeeding
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Subjects who have received any investigational medicinal product (IMP) in a clinical research study within the 90 days prior to Day 1 (Part 1) or Day 1 of Period 1 (Part
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History of serious adverse reaction or serious hypersensitivity to any drug or allergy to the study drug formulation excipients
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Subjects who are, or are immediate family members of, a study site or Sponsor employee
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Subjects who have previously been administered IMP in this study. Subjects who have taken part in Part 1 are not permitted to take part in Part 2.
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Evidence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., the virus that causes COVID-19) infection
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Positive for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at screening
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History of any drug or alcohol abuse in the past 2 years
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Regular alcohol consumption >14 units per week
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A confirmed positive alcohol breath test at screening or admission
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Current smokers and those who have smoked within the last 12 months
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Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
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Confirmed positive drugs of abuse test result at screening or admission
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Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study (Part 1 only)
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Subjects who do not have suitable veins for multiple venipunctures/cannulation as assessed by the Investigator or delegate at screening
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Clinically significant abnormal clinical chemistry, hematology, coagulation or urinalysis as judged by the Investigator
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Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <70 mL/min using the Cockcroft-Gault equation
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History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal (GI) disease (especially peptic ulceration, GI bleeding, ulcerative colitis, Crohn's Disease or Irritable Bowel Syndrome), neurological or psychiatric disorder, as judged by the Investigator
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Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator
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Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood
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Subjects who are taking, or have taken, any medication (e.g., prescription drugs, over-the-counter drugs, hormone replacement therapy [HRT], vaccines, topical medications, herbal or homeopathic remedies, nutritional supplements), other than up to 4 g of paracetamol per day, in the 14 days before IMP administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the Investigator.
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Subjects who are taking, or have taken, oral antibiotics within 4 weeks or IV antibiotics within 8 weeks prior to admission
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Subjects who are taking, or have taken, any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to admission
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History of GI surgery (with the exception of appendectomy unless it was performed within the previous 12 months) (Part 1 only)
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Acute diarrhea or constipation in the 7 days before the predicted Day 1. If screening occurs >7 days before the Day 1, this criterion will be determined on Day 1. Diarrhea will be defined as the passage of liquid feces and/or a stool frequency of greater than 3 times per day. Constipation will be defined as a failure to open the bowels for 3 days (Part 1 only)
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Malabsorption syndrome or other condition that would interfere with enteral absorption
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History or presence of an abnormal ECG that is clinically significant in the Investigator's opinion, including complete left bundle branch block, second- or third-degree atrioventricular heart block, or evidence of prior myocardial infarction
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QT interval corrected through use of Fridericia's formula (QTcF) >440 msec demonstrated by at least two ECGs >30 minutes apart
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History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
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Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 bpm prior to enrollment
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Current treatment with medications that are well known to prolong the QT interval
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Absolute neutrophil count <1.3 x 10^9/L (1300/μL)
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Failure to satisfy the Investigator of fitness to participate for any other reason
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Quotient Sciences | Nottingham | United Kingdom | NG11 6JS |
Sponsors and Collaborators
- Genentech, Inc.
Investigators
- Study Director: Clinical Trials, Genentech, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GP42662
- 2020-004650-29