Phase 1
Completed N=16
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
Healthy Volunteers
Source: ClinicalTrials.gov NCT04680273 ↗
Enrolled (actual)
16
Serious AEs
0.0%
Results posted
Feb 2023
Primary outcomePrimary: 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 — 2.78; 20.70; 23.50 milligram equivalent of free drug
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
2.78; 20.70; 23.50 | — |
| PRIMARY 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 |
9.039; 67.410; 77.012 | — |
| PRIMARY 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 |
668000; 307000; 6980; 982000; 410000; 1980000 | — |
| PRIMARY 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 |
975000; 6980; 982000; 1380000; 1980000; 3370000 | — |
| PRIMARY 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 |
2.172; 0.997; 0.023; 3.191; 1.331; 6.428 | — |
| PRIMARY 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) by Cumulative Collection Interval |
3.169; 0.023; 3.191; 4.500; 6.451; 10.950 | — |
| PRIMARY Part 1: Maximum Observed Concentration (Cmax), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood |
74.3; 124; 88.0 | — |
| PRIMARY Part 1: Time to Maximum Observed Concentration (Tmax), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood |
3.50; 5.00; 5.00 | — |
| PRIMARY 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 |
1930; 3370; 2530 | — |
| PRIMARY 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 |
2600; 4160; 3280 | — |
| PRIMARY 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 |
2680; 6480 | — |
| PRIMARY Part 1: Terminal Elimination Half-Life (t1/2), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole Blood |
42.6; 48.4; 50.8 | — |
| PRIMARY 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 |
0.0163; 0.0143; 0.0136 | — |
| PRIMARY 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 |
11.5 | — |
| PRIMARY Part 1: Apparent Volume of Distribution Where Fraction of Dose Bioavailable is Unknown (Vz/F), Estimated for GDC-9545 in Plasma |
705 | — |
| PRIMARY Part 1: Total Radioactivity Concentrations of [14C]-GDC-9545 in Plasma and Whole Blood at Specified Timepoints |
64.7; 48.4; 88.1; 66.7; 111; 74.3 | — |
| PRIMARY Part 1: Whole Blood to Plasma Total Radioactivity Concentration Ratios of [14C]-GDC-9545 at Specified Timepoints |
0.747; 0.758; 0.673; 0.732; 0.704; 0.738 | — |
| PRIMARY 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 |
58.06; 58.70 | — |
| PRIMARY Part 2: Relative Bioavailability Based on the Adjusted Cmax (Frel Cmax) of the GDC-9545/F18 Capsule Calculated Relative to the GDC-9545/F12 Capsule, Estimated in Plasma Samples |
100.79 | — |
| PRIMARY Part 2: Relative Bioavailability Based on the Adjusted AUC(0-∞) [Frel AUC(0-∞)] of the GDC-9545/F18 Capsule Calculated Relative to the GDC-9545/F12 Capsule, Estimated in Plasma Samples |
102.04 | — |
| PRIMARY Part 2: Relative Bioavailability Based on the Adjusted AUC(0-t) [Frel AUC(0-t)] of GDC-9545/F18 Capsule Calculated Relative to GDC-9545/F12 Capsule, Estimated in Plasma Samples |
101.97 | — |
| SECONDARY Part 2: Cmax for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
804; 94.1; 93.8 | — |
| SECONDARY Part 2: Tmax for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
0.50; 5.00; 4.00 | — |
| SECONDARY Part 2: AUC(0-t) for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
5700; 3120; 3150 | — |
| SECONDARY Part 2: AUC(0-∞) for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
5630; 3270; 3300 | — |
| SECONDARY Part 2: t1/2 for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
37.8; 35.2; 36.4 | — |
| SECONDARY Part 2: First Order Rate Constant Associated With Terminal Portion of the Curve (λz) for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
0.0184; 0.0197; 0.0191 | — |
| SECONDARY Part 2: Total Body Clearance (CL) After a Single IV Administration for GDC-9545 Solution for Infusion, Estimated in Plasma Samples |
5.31 | — |
| SECONDARY Part 2: Total Body Clearance Calculated After a Single Extravascular Administration Where Fraction of Dose Bioavailable is Unknown (CL/F) for GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
9.18; 9.08 | — |
| SECONDARY Part 2: Volume of Distribution Based on the Terminal Phase Calculated Using AUC(0-∞) After a Single IV Administration (Vz) for GDC-9545 Solution for Infusion, Estimated in Plasma Samples |
266 | — |
| SECONDARY Part 2: Apparent Volume of Distribution Based on the Terminal Phase Calculated With AUC(0-∞) After a Single Extravascular Administration Where Fraction of Dose Bioavailable is Unknown (Vz/F) for GDC-9545/F12 and /F18 Capsules, Estimated in Plasma Samples |
466; 476 | — |
| SECONDARY Parts 1 and 2: Number of Participants With at Least One Adverse Event, With Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) |
3; 5; 3; 4; 9; 0 | — |
| SECONDARY Parts 1 and 2: Number of Participants With at Least One Abnormality in Laboratory Safety Tests, Reported as Adverse Events |
0; 0; 0; 0 | — |
| SECONDARY Parts 1 and 2: Number of Participants With at Least One Abnormality in Vital Sign Measurements, Reported as Adverse Events |
0; 0; 0; 0 | — |
| SECONDARY Parts 1 and 2: Number of Participants With at Least One Abnormality in 12-Lead Electrocardiogram Measurements, Reported as Adverse Events |
0; 0; 0; 0 | — |
Eligibility 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)
- 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 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/μ
Data sourced from ClinicalTrials.gov (NCT04680273). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.