Healthy Volunteers
Conditions
Brief summary
The primary objective of Part 1 of this study is to evaluate the safety and tolerability of the intravenous (IV) dose of GDC-0973. The primary objectives of Part 2 of this study are to evaluate the absolute bioavailability of GDC-0973 and to evaluate the pharmacokinetic (PK) of GDC-0973 following IV and oral administration. The secondary objective of Part 2 of this study is to evaluate the safety of GDC-0973 administered orally and intravenously.
Interventions
DRUGGDC-0973 IV Infusion
IV infusion.
DRUGGDC-0973 Oral Capsules
Oral dose.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Within body mass index range 18.5 to 29.9 kilograms per square meter (kg/m\^2) * In good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), and vital signs * Clinical laboratory evaluations within the reference range for the test laboratory * Negative test for selected drugs of abuse at Screening and at each Check-in * Negative hepatitis panel and anti-hepatitis C virus and negative human immunodeficiency virus (HIV) antibody screens * Healthy males and females of non-child-bearing potential or who agree to use effective contraception
Exclusion criteria
* Significant history or clinical manifestation of any significant metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder * History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance * History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs except that appendectomy, hernia repair, and cholecystectomy will be allowed * History or presence of an abnormal ECG * History of alcoholism or drug addiction prior to period 1 check-in * Use of any tobacco-containing or nicotine-containing products prior to period 1 check-in * Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 28 days or 5 half-lives, whichever is longer, prior to period 1 check-in * Use of any prescription medications/products, including proton pump inhibitors, within 14 days prior to period 1 check-in * Poor peripheral venous access * Any acute or chronic condition that would limit the participants ability to complete and/or participate in this clinical study * Female participant is pregnant, lactating, or breastfeeding * Predisposing factors to retinal vein occlusion (RVO)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973 | Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | — |
| Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | Cmax(dn) is Cmax divided by dose. |
| Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | — |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). |
| Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). AUC (0-t)dn is AUC (0-t) divided by dose. |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | AUC (0 - ∞)= Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). |
| Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞)dn is AUC(0 - ∞) divided by dose. |
| Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | t1/2 is the time measured for the plasma concentration of GDC-0973 to decrease by one half. |
| Systemic Clearance (CL) of IV GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. |
| Apparent Oral Clearance (CL/F) of Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modelling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Volume of Distribution at Steady State (Vss) of IV GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state. |
| Apparent Volume of Distribution (Vz/F) of Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed. |
| Absolute Oral Bioavailability (F) of GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | Absolute oral bioavailability is the amount of drug from a formulation that reaches the systemic circulation relative to an IV dose. F = \[AUC (0-∞), oral multiplied by Dose IV\] divided by \[AUC (0-∞), IV multiplied by Dose oral\]. Absolute oral bioavailability is determined for drugs which are administered orally. IV dose is 100% in systemic circulation (dosed directly) and hence no estimation is required. |
| Mean Absorption Time (MAT) | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 | MAT is mean time required for the drug to reach the central compartment. MAT was estimated from the mean resident time (MRT) from oral and IV administration. MAT was calculated as MRT last of oral dose minus MRT last of IV dose. MAT is analyzed when drug is administered orally (only for non-IV routes of administration). |
| Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973 | Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1 | The cumulative amount of drug excreted in urine over the entire collection interval of 96 hrs was calculated by adding the Aeu of the intervals 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 hrs where Aeu was calculated by multiplying the urine volume within the collection interval by the associated drug concentration. |
| Renal Clearance (CLR) of IV and Oral GDC-0973 | Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine | CLR was calculated as Aeu divided by AUC (0 - ∞), where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose and AUC(0 - ∞) was area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity hrs post-dose. |
| Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973 | Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose | % Excreted is the mean percentage of dose recovery in urine and calculated as: (Aeu divided by dose) multiplied by 100, where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose. |
Participant flow
Pre-assignment details
The study was divided into two parts. In part 1 of the study, safety of GDC-0973 was evaluated and in part 2 pharmacokinetics (PK) of GDC-0973 was evaluated. All PK outcomes apply only to part 2 of the study while safety applies to part 1 and 2 both.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Part 1: Participants received single dose of GDC-0973 2 mg IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. There was a washout period of minimum 10 days after each intervention period.
Part 2: Participants received single dose of GDC-0973 2 mg IV infusion and GDC-0973 20 mg oral capsules (four 5-mg capsules) in either of the two intervention periods. There was a washout period of minimum 10 days after each intervention period. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Washout Period | Physician Decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 35 Years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 13 | 3 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Absolute Oral Bioavailability (F) of GDC-0973
Absolute oral bioavailability is the amount of drug from a formulation that reaches the systemic circulation relative to an IV dose. F = \[AUC (0-∞), oral multiplied by Dose IV\] divided by \[AUC (0-∞), IV multiplied by Dose oral\]. Absolute oral bioavailability is determined for drugs which are administered orally. IV dose is 100% in systemic circulation (dosed directly) and hence no estimation is required.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population who received oral dose of GDC-0973.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Absolute Oral Bioavailability (F) of GDC-0973 | 0.457 Ratio | Geometric Coefficient of Variation 25 |
Primary
Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973
The cumulative amount of drug excreted in urine over the entire collection interval of 96 hrs was calculated by adding the Aeu of the intervals 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 hrs where Aeu was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.
Time frame: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973 | 0.0761 mg | Geometric Coefficient of Variation 22.3 |
| GDC-0973 20 mg Oral | Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973 | 0.379 mg | Geometric Coefficient of Variation 33.9 |
Primary
Apparent Oral Clearance (CL/F) of Oral GDC-0973
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modelling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population who received oral dose of GDC-0973.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Apparent Oral Clearance (CL/F) of Oral GDC-0973 | 23.0 L/hr | Geometric Coefficient of Variation 29.5 |
Primary
Apparent Volume of Distribution (Vz/F) of Oral GDC-0973
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population who received oral dose of GDC-0973.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Apparent Volume of Distribution (Vz/F) of Oral GDC-0973 | 2197 Liter | Geometric Coefficient of Variation 31.9 |
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973
AUC (0 - ∞)= Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973 | 188 ng*hr/mL | Geometric Coefficient of Variation 16.2 |
| GDC-0973 20 mg Oral | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973 | 784 ng*hr/mL | Geometric Coefficient of Variation 29.5 |
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973
AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973 | 156 ng*hr/mL | Geometric Coefficient of Variation 19.1 |
| GDC-0973 20 mg Oral | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973 | 688 ng*hr/mL | Geometric Coefficient of Variation 28.4 |
Primary
Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973
AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞)dn is AUC(0 - ∞) divided by dose.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973 | 93.9 ng*hr/mL/mg | Geometric Coefficient of Variation 16.2 |
| GDC-0973 20 mg Oral | Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973 | 43.5 ng*hr/mL/mg | Geometric Coefficient of Variation 29.5 |
Comparison: LS mean was calculated from ANOVA. Data for dose-normalized AUC (0 - ∞) were natural log-transformed prior to analysis.90% CI: [39.74, 53.06]
Primary
Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973
AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). AUC (0-t)dn is AUC (0-t) divided by dose.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973 | 77.8 ng*hr/mL/mg | Geometric Coefficient of Variation 19.1 |
| GDC-0973 20 mg Oral | Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973 | 38.2 ng*hr/mL/mg | Geometric Coefficient of Variation 28.4 |
Comparison: LS means was calculated from ANOVA. Data for dose-normalized AUC (0 - t) were natural log-transformed prior to analysis.90% CI: [41.43, 56.94]
Primary
Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973
Cmax(dn) is Cmax divided by dose.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973 | 10.2 ng/mL/mg | Geometric Coefficient of Variation 35.6 |
| GDC-0973 20 mg Oral | Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973 | 0.844 ng/mL/mg | Geometric Coefficient of Variation 26.4 |
Comparison: Least squares (LS) mean was calculated from analysis of variance (ANOVA). Data for dose-normalized Cmax were natural log-transformed prior to analysis.90% CI: [7.08, 10.08]
Primary
Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973
Time frame: Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population included participants who were randomized, received study drug, and had at least 1 valid PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973 | 20.5 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.6 |
| GDC-0973 20 mg Oral | Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973 | 15.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26.4 |
Primary
Mean Absorption Time (MAT)
MAT is mean time required for the drug to reach the central compartment. MAT was estimated from the mean resident time (MRT) from oral and IV administration. MAT was calculated as MRT last of oral dose minus MRT last of IV dose. MAT is analyzed when drug is administered orally (only for non-IV routes of administration).
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population who received oral dose of GDC-0973. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Mean Absorption Time (MAT) | 2.67 hr | Geometric Coefficient of Variation 58 |
Primary
Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973 | 0.261 ng/mL | Geometric Coefficient of Variation 37.1 |
| GDC-0973 20 mg Oral | Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973 | 0.546 ng/mL | Geometric Coefficient of Variation 70 |
Primary
Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973
% Excreted is the mean percentage of dose recovery in urine and calculated as: (Aeu divided by dose) multiplied by 100, where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose.
Time frame: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973 | 3.81 Percent dose excreted | Geometric Coefficient of Variation 22.3 |
| GDC-0973 20 mg Oral | Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973 | 1.90 Percent dose excreted | Geometric Coefficient of Variation 33.9 |
Primary
Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973
t1/2 is the time measured for the plasma concentration of GDC-0973 to decrease by one half.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973 | 73.8 hr | Geometric Coefficient of Variation 17.1 |
| GDC-0973 20 mg Oral | Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973 | 66.2 hr | Geometric Coefficient of Variation 18.2 |
Primary
Renal Clearance (CLR) of IV and Oral GDC-0973
CLR was calculated as Aeu divided by AUC (0 - ∞), where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose and AUC(0 - ∞) was area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity hrs post-dose.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine
Population: Full analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Renal Clearance (CLR) of IV and Oral GDC-0973 | 0.405 L/hr | Geometric Coefficient of Variation 20.1 |
| GDC-0973 20 mg Oral | Renal Clearance (CLR) of IV and Oral GDC-0973 | 0.484 L/hr | Geometric Coefficient of Variation 22.4 |
Primary
Systemic Clearance (CL) of IV GDC-0973
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population who received IV dose of GDC-0973.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Systemic Clearance (CL) of IV GDC-0973 | 10.7 Liter (L)/hr | Geometric Coefficient of Variation 16.2 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Population: Full analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GDC-0973 2 mg IV | Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973 | 0.500 hr |
| GDC-0973 20 mg Oral | Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973 | 4.00 hr |
Primary
Volume of Distribution at Steady State (Vss) of IV GDC-0973
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state.
Time frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1
Population: Full analysis population who received IV dose of GDC-0973.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GDC-0973 2 mg IV | Volume of Distribution at Steady State (Vss) of IV GDC-0973 | 1052 Liter | Geometric Coefficient of Variation 28.2 |