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

Genentech, Inc.16 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Healthy Volunteers

Interventions

[14C]-GDC-9545

Eligibility

Sex: FEMALEMin age: 30 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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) * A body mass index (BMI) between 18.5 and 32.0 kg/m\^2, inclusive, at screening * Ability to comply with the study protocol * Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day) (Part 1 only) Exclusion Criteria: * Women of childbearing potential, women who are pregnant or breastfeeding * 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 2) * History of serious adverse reaction or serious hypersensitivity to any drug or allergy to the study drug formulation excipients * Subjects who are, or are immediate family members of, a study site or Sponsor employee * 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. * Evidence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., the virus that causes COVID-19) infection * Positive for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at screening * History of any drug or alcohol abuse in the past 2 years * Regular alcohol consumption \>14 units per week * A confirmed positive alcohol breath test at screening or admission * Current smokers and those who have smoked within the last 12 months * Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months * Confirmed positive drugs of abuse test result at screening or admission * 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) * Subjects who do not have suitable veins for multiple venipunctures/cannulation as assessed by the Investigator or delegate at screening * Clinically significant abnormal clinical chemistry, hematology, coagulation or urinalysis as judged by the Investigator * Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of \<70 mL/min using the Cockcroft-Gault equation * 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 * Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator * Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood * 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. * Subjects who are taking, or have taken, oral antibiotics within 4 weeks or IV antibiotics within 8 weeks prior to admission * 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 * History of GI surgery (with the exception of appendectomy unless it was performed within the previous 12 months) (Part 1 only) * 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) * Malabsorption syndrome or other condition that would interfere with enteral absorption * 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 * QT interval corrected through use of Fridericia's formula (QTcF) \>440 msec demonstrated by at least two ECGs \>30 minutes apart * 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 * Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 bpm prior to enrollment * Current treatment with medications that are well known to prolong the QT interval * Absolute neutrophil count \<1.3 x 10\^9/L (1300/μL) * Failure to satisfy the Investigator of fitness to participate for any other reason

Outcomes

Primary Outcomes

Part 1: Mean Cumulative Amount of Total Radioactivity (CumAe) of [14C]-GDC-9545 Excreted in Urine, Feces, and Total (Urine and Feces Combined) Over the Entire Collection Period

Following a single oral dose of 30 milligrams of \[14C\]-GDC-9545, urine and fecal samples were collected over time from each participant. The amounts of total radioactivity excreted in the samples were determined using liquid scintillation counting. The lower limits of detection in urine and fecal samples were 0.423 and 8.36 nanogram equivalent of free drug per gram of sample, respectively. Following Day 21 (480 hours), where urine/fecal collections were no longer continuous and spot sampling days commenced, interpolation of Ae was calculated to estimate the amount excreted on non-collection days (collection intervals with interpolated values included 480-648 hours, 672-816 hours, and 840-984 hours).

Time frame: From Day 1 to Day 42 (0-1008 hours)

Part 1: Mean Cumulative Amount of Total Radioactivity Expressed as a Percentage of the Radioactive Dose Administered (CumFe) of [14C]-GDC-9545 Recovered in Urine, Feces, and Total (Urine and Feces Combined) Over the Entire Collection Period

Time frame: From Day 1 to Day 42 (0-1008 hours)

Part 1: Mean Amount of Total Radioactivity (Ae) of [14C]-GDC-9545 Excreted in Urine, Feces, and Total (Urine and Feces Combined) by Collection Interval

Time frame: 0-12, 12-24, 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312, 312-336, 336-360, 360-384, 384-408, 408-432, 432-456, 456-480, 480-648, 648-672, 672-816, 816-840, 840-984, & 984-1008 hours

Part 1: Mean Cumulative Amount of Total Radioactivity (CumAe) of [14C]-GDC-9545 Excreted in Urine, Feces, and Total (Urine and Feces Combined) by Cumulative Collection Interval

Time frame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144, 0-168, 0-192, 0-216, 0-240, 0-264, 0-288, 0-312, 0-336, 0-360, 0-384, 0-408, 0-432, 0-456, 0-480, 0-648, 0-672, 0-816, 0-840, 0-984, and 0-1008 hours

Part 1: Mean Amount of Total Radioactivity Expressed as a Percentage of the Radioactive Dose Administered (Fe) of [14C]-GDC-9545 Recovered in Urine, Feces, and Total (Urine and Feces Combined) by Collection Interval

Time frame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144, 0-168, 0-192, 0-216, 0-240, 0-264, 0-288, 0-312, 0-336, 0-360, 0-384, 0-408, 0-432, 0-456, 0-480, 0-648, 0-672, 0-816, 0-840, 0-984, and 0-1008 hours

Part 1: Maximum Observed Concentration (Cmax), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Pharmacokinetic parameters were estimated where possible and appropriate for each participant profile by non-compartmental analysis methods using Phoenix WinNonlin software. Plasma concentrations of GDC-9545 were determined using liquid chromatography with tandem mass spectrometry. Total radioactivity concentrations in plasma and whole blood were determined using liquid scintillation counting. The unit of measure for the total radioactivity concentrations is nanogram equivalent of free drug per millilitre.

Time frame: 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), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Time frame: 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 72 Hours [AUC(0-72)], Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Time frame: Pre-dose and post-dose at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours

Part 1: Area Under the Concentration-Time Curve From Time 0 to the Time of Last Measurable Concentration [AUC(0-t)], Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Time frame: 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 [AUC(0-∞)], Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma

Pharmacokinetic parameters were estimated where possible and appropriate for each participant profile by non-compartmental analysis methods using Phoenix WinNonlin software. Plasma concentrations of GDC-9545 were determined using liquid chromatography with tandem mass spectrometry. Total radioactivity (TR) concentrations in plasma and whole blood were determined using liquid scintillation counting.

Time frame: 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), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Pharmacokinetic parameters were estimated where possible and appropriate for each participant profile by non-compartmental analysis methods using Phoenix WinNonlin software. Plasma concentrations of GDC-9545 were determined using liquid chromatography with tandem mass spectrometry. Total radioactivity (TR) concentrations in plasma and whole blood were determined using liquid scintillation counting.

Time frame: 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: First Order Rate Constant Associated With Terminal Portion of the Curve (λz), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood

Time frame: 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: Total Body Clearance Calculated After a Single Extravascular Administration Where Fraction of Dose Bioavailable is Unknown (CL/F), Estimated for GDC-9545 in Plasma

Time frame: 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: Apparent Volume of Distribution Where Fraction of Dose Bioavailable is Unknown (Vz/F), Estimated for GDC-9545 in Plasma

Time frame: 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: Total Radioactivity Concentrations of [14C]-GDC-9545 in Plasma and Whole Blood at Specified Timepoints

Total radioactivity concentrations in plasma and whole blood were determined using liquid scintillation counting. For calculation of the geometric mean, values reported as not detectable have been set to 0.5× the limit of detection (LOD); the LOD was 11.0 nanogram equivalent of free drug per millilitre (mL).

Time frame: Postdose at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours

Part 1: Whole Blood to Plasma Total Radioactivity Concentration Ratios of [14C]-GDC-9545 at Specified Timepoints

Total radioactivity concentrations in plasma and whole blood were determined using liquid scintillation counting. The limit of detection was 11.0 nanogram equivalent of free drug per millilitre (mL).

Time frame: Postdose at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours

Part 2: Absolute Bioavailability (F) of GDC-9545/F12 and /F18 Capsules Calculated Relative to GDC-9545 Solution for Infusion Based on the Adjusted AUC(0-∞), Estimated in Plasma Samples

Absolute bioavailability of the GDC-9545/F12 and /F18 capsules were calculated relative to GDC-9545 solution for infusion based on the adjusted geometric mean AUC(0-∞) values obtained after oral and intravenous (IV) administration of GDC-9545. Log-transformed AUC(0-∞) was analyzed using mixed effects modelling techniques. The model included terms for treatment and sequence fitted as fixed effects and subject within sequence fitted as a random effect.