MedPath

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

Phase 1
Completed
Conditions
Healthy Volunteers
Interventions
Drug: GDC-9545 Solution for Infusion
Drug: GDC-9545/F12 Capsule
Drug: GDC-9545/F18 Capsule
Registration Number
NCT04680273
Lead Sponsor
Genentech, Inc.
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.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
Female
Target Recruitment
16
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

Study & Design

Study Type
INTERVENTIONAL
Study Design
CROSSOVER
Arm && Interventions
GroupInterventionDescription
Part 1: [14C]-GDC-9545[14C]-GDC-9545Participants will be enrolled to receive a single dose of Carbon-14 labelled \[14C\]-GDC-9545.
Part 2: GDC-9545 Treatment Sequence BCDGDC-9545 Solution for InfusionParticipants 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.
Part 2: GDC-9545 Treatment Sequence BCDGDC-9545/F12 CapsuleParticipants 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.
Part 2: GDC-9545 Treatment Sequence BCDGDC-9545/F18 CapsuleParticipants 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.
Part 2: GDC-9545 Treatment Sequence BDCGDC-9545 Solution for InfusionParticipants 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.
Part 2: GDC-9545 Treatment Sequence BDCGDC-9545/F12 CapsuleParticipants 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.
Part 2: GDC-9545 Treatment Sequence BDCGDC-9545/F18 CapsuleParticipants 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.
Primary Outcome Measures
NameTimeMethod
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 PeriodFrom Day 1 to Day 42 (0-1008 hours)

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).

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 PeriodFrom Day 1 to Day 42 (0-1008 hours)

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).

Part 1: Mean Amount of Total Radioactivity (Ae) of [14C]-GDC-9545 Excreted in Urine, Feces, and Total (Urine and Feces Combined) by Collection Interval0-12, 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

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).

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 Interval0-24, 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

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).

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 Interval0-12, 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

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).

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 Interval0-24, 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

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).

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

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.

Part 1: Time to Maximum Observed Concentration (Tmax), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole BloodPre-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

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.

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

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.

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 BloodPre-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

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.

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 PlasmaPre-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

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.

Part 1: Terminal Elimination Half-Life (t1/2), Estimated for GDC-9545 in Plasma and for Total Radioactivity in Plasma and Whole BloodPre-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

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.

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 BloodPre-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

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.

Part 1: Apparent Volume of Distribution Where Fraction of Dose Bioavailable is Unknown (Vz/F), Estimated for GDC-9545 in PlasmaPre-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

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.

Part 1: Total Radioactivity Concentrations of [14C]-GDC-9545 in Plasma and Whole Blood at Specified TimepointsPostdose at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours

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).

Part 1: Whole Blood to Plasma Total Radioactivity Concentration Ratios of [14C]-GDC-9545 at Specified TimepointsPostdose at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours

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).

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 SamplesFor 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

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.

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 SamplesFor 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

Relative bioavailability of the GDC-9545/F18 capsule was calculated relative to the GDC-9545/F12 capsule based on the adjusted geometric mean Cmax values. Log-transformed Cmax was analyzed using mixed effects modelling techniques. The model included terms for treatment, sequence, and period fitted as fixed effects and subject nested within sequence as a random effect.

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 PlasmaPre-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

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.

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 SamplesFor 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

Relative bioavailability of the GDC-9545/F18 capsule was calculated relative to the GDC-9545/F12 capsule based on the adjusted geometric mean AUC(0-∞) values. Log-transformed AUC(0-∞) was analyzed using mixed effects modelling techniques. The model included terms for treatment, sequence, and period fitted as fixed effects and subject nested within sequence as a random effect.

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 SamplesFor 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

Relative bioavailability of the GDC-9545/F18 capsule was calculated relative to the GDC-9545/F12 capsule based on the adjusted geometric mean AUC(0-t) values. Log-transformed AUC(0-t) was analyzed using mixed effects modelling techniques. The model included terms for treatment, sequence, and period fitted as fixed effects and subject nested within sequence as a random effect.

Secondary Outcome Measures
NameTimeMethod
Part 2: Cmax for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma SamplesFor 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

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.

Part 2: Tmax for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma SamplesFor 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

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.

Part 2: AUC(0-t) for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma SamplesFor 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

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.

Part 2: AUC(0-∞) for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma SamplesFor 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

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.

Part 2: t1/2 for GDC-9545 Solution for Infusion and GDC-9545/F12 and /F18 Capsules, Estimated in Plasma SamplesFor 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

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.

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 SamplesFor 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

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.

Part 2: Total Body Clearance (CL) After a Single IV Administration for GDC-9545 Solution for Infusion, Estimated in Plasma SamplesFor 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

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.

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 SamplesFor 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

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.

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 SamplesFor 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

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.

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 SamplesFor 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

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.

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)From Baseline until end of study (up to 42 days and 35 days for Parts 1 and 2, respectively)

All adverse events (AEs) were recorded and the investigator independently assessed the seriousness and severity of each AE. AE severity was graded on a scale from 1 to 5 using the NCI-CTCAE v5.0; any events not specifically listed in the scale were defined as: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening; and Grade 5 is death related to an AE. AEs of special interest were: Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law; Cases of potential drug-induced kidney injury; Grade ≥3 nausea/vomiting/diarrhea; Grade ≥2 thromboembolic events; Grade ≥3 renal failure; Grade ≥3 hepatitis or elevation in ALT or AST; Grade ≥2 vaginal or uterine hemorrhage; Grade ≥2 bradycardia; Any grade of endometrial cancer; and, Suspected transmission of an infectious agent by the study drug.

Parts 1 and 2: Number of Participants With at Least One Abnormality in Laboratory Safety Tests, Reported as Adverse EventsPart 1: Baseline and Discharge Day (up to 21 days); Part 2: Baseline, Day -1 of each of the 3 treatment periods, and Discharge Day (up to 29 days)

Participants provided blood samples at the specified timepoints for laboratory analysis of clinical chemistry, hematology, and coagulation panels (please refer to Appendices 1 and 2 of the protocol for a complete list). Any of the laboratory test results that were outside of a parameter's normal reference range were considered abnormalities. Not every laboratory abnormality qualified as an adverse event (AE). A laboratory test result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment.

Parts 1 and 2: Number of Participants With at Least One Abnormality in Vital Sign Measurements, Reported as Adverse EventsPart 1: Baseline, predose and 1, 4, and 24 hours postdose, and Discharge Day (up to 21 days); Part 2: Baseline, predose and 0.5, 1, 4, and 24 hours postdose for each of the 3 treatment periods, and Discharge Day (up to 29 days)

Vital sign measurements included pulse rate, systolic and diastolic blood pressure while the participant was in a supine position for 5 minutes, and oral temperature. Any of the vital sign results that were outside of a parameter's normal range were considered abnormalities. Not every vital sign abnormality qualified as an adverse event (AE). A vital sign result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment.

Parts 1 and 2: Number of Participants With at Least One Abnormality in 12-Lead Electrocardiogram Measurements, Reported as Adverse EventsPart 1: Baseline (Day 1, predose), 1, 4, and 24 hours postdose, and Discharge Day (up to 21 days); Part 2: Baseline (Day 1, predose), 0.5, 1, 4, and 24 hours postdose for each of the 3 treatment periods, and Discharge Day (up to 29 days)

The 12-lead electrocardiograms (ECG) recorded measurements of heart rate, and PR, RR, QRS, uncorrected QT, and QTcF intervals. Any of the ECG parameter results that were outside of the normal range were considered abnormalities. Not every ECG abnormality qualified as an adverse event (AE). An ECG result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment.

Trial Locations

Locations (1)

Quotient Sciences

🇬🇧

Nottingham, United Kingdom

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