Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Brief summary
Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD).
Interventions
DRUGGSP304 (tiotropium bromide) Inhalation Solution
Once daily (QD) oral inhalation using a nebulizer
DRUGGSP304 Placebo Inhalation Solution
Once daily (QD) oral inhalation using a nebulizer
DRUGSpiriva® Respimat® inhalation spray
Once daily (QD) oral inhalation
Sponsors
Glenmark Specialty S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects ≥40 years and ≤85 years of age at the time of consent. * Subject must have a primary diagnosis of mild or moderate COPD defined as post-bronchodilator FEV1/FVC ratio of \<70% and FEV1 of ≥50% of predicted normal value as per the NHANES III predicted normal values at screening. * Willing to stop all other COPD medications or other medications which will interfere with the study results for the entire duration of the study, except albuterol/salbutamol as needed. * Current or ex-smoker with ≥10 pack-year smoking history.
Exclusion criteria
* Subjects with a chest x-ray/CT scan that suggests a diagnosis other than COPD (eg, pneumonia, other infection, atelectasis, or pneumothorax or other active/ongoing pulmonary conditions) and taken within 6 months prior to study start. If there is no chest x-ray or CT scan taken within 6 months prior to study start, or if recent results are unavailable for review, a chest x-ray must be performed. * Use of oral/parenteral corticosteroids or antibiotics for COPD within 6 weeks or depot corticosteroids within 3 months prior to screening or subject has had a change in dose or type of any medications for COPD within 14 days before screening. * Hospitalization for COPD exacerbation or pneumonia within 3 months prior to screening. * Subjects with a history of asthma, with the exception of outgrown childhood asthma, defined as transient wheezers outgrown by 5 years of age. * Subject has a known history of alpha 1 antitrypsin deficiency-related emphysema. * Subject requires nocturnal oxygen or continuous supplemental oxygen therapy. * Subject with history of a positive result for HBsAg or HCV antibody. * Subject is known to be seropositive for human immunodeficiency virus. * Female subject is pregnant or lactating. * Subject has a history of allergic reaction to the anti-cholinergic or any components of the study medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose. | The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS) |
| Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose. | The PK endpoint in plasma to assess the relative bioavailability was area under the plasma concentration-time curve of tiotropium over the dosing interval at steady state (AUC0-tauSS) |
| Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 21 days (Pre- dose trough FEV1 is mean FEV1 at -45 mins and -15 mins pre-morning dose at Day 1. Trough FEV1 is mean FEV1 obtained 23 hrs 15 mins and 23 hrs 45 mins post-morning dose of day 21). | Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes postdose measurements), in comparison with placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Day 21 | Descriptive statistics for tiotropium urine PK parameter-Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 |
| Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | Day 1 | Descriptive statistics for tiotropium plasma PK parameters - (Cmax) on Day 1 |
| Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | Day 1 | Descriptive statistics for tiotropium plasma PK parameter - Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1 |
| Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | Day 1 | Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 1 |
| Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | Day 21 | Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 21 |
| Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | Day 21 | Descriptive statistics for tiotropium plasma PK parameter - Average concentration during a dosing interval at steady state (CavSS) on day 21 |
| Accumulation Ratio Rac(Auc) | Day 21 | Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(auc). Rac(auc) was calculated as AUC0-tauSS/AUC0-tau. |
| Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | Day 1 | Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of tiotropium excreted in urine over the dosing interval on Day 1 |
| Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 1. Change from baseline in peak FEV1 within 12 hours postdose on Day 1 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. |
| Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 21. Change from baseline in peak FEV1 within 12 hours postdose on Day 21 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. |
| Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | Day 1 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 1. Postdose timing were relative to the end of dosing.The window for 1 hour spirometry and thereafter was ±5 minutes). | Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 1. |
| Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | Day 21 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 21. Postdose timing were relative to the end of dosing. The window for 1 hour spirometry and thereafter was ±5 minutes). | Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 21 |
| Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1. |
| Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose). | Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 Measured Over 12 Hours on Day 21. |
| Accumulation Ratio Rac(Cmax) | Day 21 | Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(cmax). Rac(Cmax) was calculated as CmaxSS/Cmax. |
| Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | Day 21 | Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 |
| Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | Day 1 | Descriptive statistics for tiotropium urine PK parameter - Fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1 |
Countries
United States
Participant flow
Pre-assignment details
A total of 155 subjects were randomized to study treatments.
Participants by arm
| Arm | Count |
|---|---|
| GSP304 10 μg Oral inhalation, once daily (morning) for 21 days | 30 |
| GSP304 20 μg Oral inhalation, once daily (morning) for 21 days | 32 |
| GSP304 40 μg Oral inhalation, once daily (morning) for 21 days | 31 |
| Placebo Oral inhalation, once daily (morning) for 21 days | 32 |
| SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days | 30 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 1 | 1 |
| Overall Study | COPD Exacerbation | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Non compliance with Study Procedures | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Sponsor Decision | 1 | 0 | 1 | 0 | 1 |
| Overall Study | Violation of Inclusion/ExclusionCriteria | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | GSP304 10 μg | GSP304 20 μg | GSP304 40 μg | Placebo | SPIRIVA RESPIMAT 5 μg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 7.12 | 61.6 years STANDARD_DEVIATION 10.34 | 65.4 years STANDARD_DEVIATION 10.02 | 65.0 years STANDARD_DEVIATION 9.51 | 62.0 years STANDARD_DEVIATION 9.42 | 63.4 years STANDARD_DEVIATION 9.38 |
| BMI | 25.848 kg/m^2 STANDARD_DEVIATION 2.8936 | 26.150 kg/m^2 STANDARD_DEVIATION 4.0007 | 24.799 kg/m^2 STANDARD_DEVIATION 3.7138 | 25.409 kg/m^2 STANDARD_DEVIATION 3.5321 | 25.503 kg/m^2 STANDARD_DEVIATION 3.1809 | 25.543 kg/m^2 STANDARD_DEVIATION 3.4803 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 29 Participants | 27 Participants | 31 Participants | 28 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 25 Participants | 29 Participants | 31 Participants | 29 Participants | 141 Participants |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 14 Participants | 17 Participants | 20 Participants | 75 Participants |
| Sex: Female, Male Male | 17 Participants | 21 Participants | 17 Participants | 15 Participants | 10 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 32 | 0 / 31 | 0 / 33 | 0 / 30 |
| other Total, other adverse events | 3 / 30 | 6 / 32 | 5 / 31 | 4 / 33 | 6 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 32 | 0 / 31 | 0 / 33 | 0 / 30 |
Outcome results
Primary
Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo.
Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes postdose measurements), in comparison with placebo.
Time frame: 21 days (Pre- dose trough FEV1 is mean FEV1 at -45 mins and -15 mins pre-morning dose at Day 1. Trough FEV1 is mean FEV1 obtained 23 hrs 15 mins and 23 hrs 45 mins post-morning dose of day 21).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 0.14 L | Standard Error 0.04 |
| GSP304 20 μg | Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 0.10 L | Standard Error 0.04 |
| GSP304 40 μg | Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 0.09 L | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 0.08 L | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo. | 0.14 L | Standard Error 0.04 |
Comparison: GSP 304 vs Placebo comparison for change from baseline in trough FEV1 was tested at 0.05 significance level.p-value: 0.22895% CI: [-0.04, 0.17]MMRM
Comparison: GSP 304 vs Placebo comparison for change from baseline in trough FEV1 was tested at 0.05 significance level.p-value: 0.65595% CI: [-0.08, 0.13]MMRM
Comparison: GSP 304 vs Placebo comparison for change from baseline in trough FEV1 was tested at 0.05 significance level.p-value: 0.89495% CI: [-0.1, 0.11]MMRM
Comparison: SPIRIVA RESPIMAT 5 μg vs Placebo comparison for change from baseline in trough FEV1 was tested at 0.05 significance level.p-value: 0.2695% CI: [-0.04, 0.16]MMRM
Primary
Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS
The PK endpoint in plasma to assess the relative bioavailability was area under the plasma concentration-time curve of tiotropium over the dosing interval at steady state (AUC0-tauSS)
Time frame: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.
Population: The PK analysis set consisted of all subjects who were randomized, received at least 1 dose of study treatment, and had at least 1 quantifiable PK sample and did not have an exclusionary major protocol deviation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | 22.90 h*pg/mL | Standard Error 1.13 |
| GSP304 20 μg | Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | 49.10 h*pg/mL | Standard Error 1.123 |
| GSP304 40 μg | Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | 122.00 h*pg/mL | Standard Error 1.13 |
| SPIRIVA RESPIMAT 5 μg | Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS | 57.70 h*pg/mL | Standard Error 1.13 |
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on AUC0-tauSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [29.79, 52.87]
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on AUC0-tauSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [64.43, 112.64]
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on AUC0-tauSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [158.8, 281.8]
Primary
Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS
The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS)
Time frame: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.
Population: The PK analysis set consisted of all subjects who were randomized, received at least 1 dose of study treatment, and had at least 1 quantifiable PK sample and did not have an exclusionary major protocol deviation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | 4.10 pg/mL | Standard Error 1.152 |
| GSP304 20 μg | Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | 8.00 pg/mL | Standard Error 1.14 |
| GSP304 40 μg | Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | 21.80 pg/mL | Standard Error 1.152 |
| SPIRIVA RESPIMAT 5 μg | Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS | 14.00 pg/mL | Standard Error 1.152 |
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on CmaxSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [21.14, 41]
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on CmaxSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [41.37, 78.46]
Comparison: GSP 304 vs SPIRIVA RESPIMAT 5 μg comparison for relative bioavailability data based on CmaxSS was tested and the estimated treatment ratios for the treatment comparisons was presented.90% CI: [111.88, 216.99]
Secondary
Accumulation Ratio Rac(Auc)
Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(auc). Rac(auc) was calculated as AUC0-tauSS/AUC0-tau.
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Accumulation Ratio Rac(Auc) | 2.966 ratio | Standard Deviation 1.561 |
| GSP304 20 μg | Accumulation Ratio Rac(Auc) | 5.328 ratio | Standard Deviation 13.53 |
| GSP304 40 μg | Accumulation Ratio Rac(Auc) | 3.667 ratio | Standard Deviation 2.873 |
| SPIRIVA RESPIMAT 5 μg | Accumulation Ratio Rac(Auc) | 3.699 ratio | Standard Deviation 2.897 |
Secondary
Accumulation Ratio Rac(Cmax)
Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(cmax). Rac(Cmax) was calculated as CmaxSS/Cmax.
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Accumulation Ratio Rac(Cmax) | 2.063 ratio | Standard Deviation 0.7187 |
| GSP304 20 μg | Accumulation Ratio Rac(Cmax) | 3.492 ratio | Standard Deviation 7.436 |
| GSP304 40 μg | Accumulation Ratio Rac(Cmax) | 2.622 ratio | Standard Deviation 2.059 |
| SPIRIVA RESPIMAT 5 μg | Accumulation Ratio Rac(Cmax) | 2.835 ratio | Standard Deviation 2.612 |
Secondary
Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1
Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of tiotropium excreted in urine over the dosing interval on Day 1
Time frame: Day 1
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 138600 pg | Standard Deviation 76830 |
| GSP304 20 μg | Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 336100 pg | Standard Deviation 233800 |
| GSP304 40 μg | Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 602900 pg | Standard Deviation 422400 |
| SPIRIVA RESPIMAT 5 μg | Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 247400 pg | Standard Deviation 219600 |
Secondary
Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21
Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 375400 pg | Standard Deviation 286900 |
| GSP304 20 μg | Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 647100 pg | Standard Deviation 460000 |
| GSP304 40 μg | Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 1611000 pg | Standard Deviation 1013000 |
| SPIRIVA RESPIMAT 5 μg | Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 775500 pg | Standard Deviation 458000 |
Secondary
Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1
Descriptive statistics for tiotropium plasma PK parameter - Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1
Time frame: Day 1
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | 10.65 pg*h/mL | Standard Deviation 7.049 |
| GSP304 20 μg | Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | 22.94 pg*h/mL | Standard Deviation 13.09 |
| GSP304 40 μg | Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | 52.11 pg*h/mL | Standard Deviation 34.7 |
| SPIRIVA RESPIMAT 5 μg | Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1 | 22.64 pg*h/mL | Standard Deviation 10.69 |
Secondary
Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21
Descriptive statistics for tiotropium plasma PK parameter - Average concentration during a dosing interval at steady state (CavSS) on day 21
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | 1.120 pg/mL | Standard Deviation 0.8301 |
| GSP304 20 μg | Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | 2.436 pg/mL | Standard Deviation 1.623 |
| GSP304 40 μg | Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | 6.273 pg/mL | Standard Deviation 4.052 |
| SPIRIVA RESPIMAT 5 μg | Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21 | 2.725 pg/mL | Standard Deviation 1.289 |
Secondary
Change From Baseline in Forced Vital Capacity (FVC) on Day 1
Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 1.
Time frame: Day 1 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 1. Postdose timing were relative to the end of dosing.The window for 1 hour spirometry and thereafter was ±5 minutes).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | 0.21 Litre | Standard Error 0.05 |
| GSP304 20 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | 0.21 Litre | Standard Error 0.05 |
| GSP304 40 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | 0.18 Litre | Standard Error 0.05 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | 0.13 Litre | Standard Error 0.05 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 1 | 0.16 Litre | Standard Error 0.05 |
p-value: 0.16695% CI: [-0.04, 0.21]Mixed Models Analysis
p-value: 0.18295% CI: [-0.04, 0.21]Mixed Models Analysis
p-value: 0.40195% CI: [-0.07, 0.17]Mixed Models Analysis
p-value: 0.57495% CI: [-0.09, 0.16]Mixed Models Analysis
Secondary
Change From Baseline in Forced Vital Capacity (FVC) on Day 21
Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 21
Time frame: Day 21 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 21. Postdose timing were relative to the end of dosing. The window for 1 hour spirometry and thereafter was ±5 minutes).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | 0.16 Litre | Standard Error 0.06 |
| GSP304 20 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | 0.10 Litre | Standard Error 0.06 |
| GSP304 40 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | 0.11 Litre | Standard Error 0.06 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | 0.11 Litre | Standard Error 0.06 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Forced Vital Capacity (FVC) on Day 21 | 0.16 Litre | Standard Error 0.06 |
p-value: 0.49395% CI: [-0.1, 0.21]Mixed Models Analysis
p-value: 0.86495% CI: [-0.17, 0.14]Mixed Models Analysis
p-value: 0.97895% CI: [-0.16, 0.15]Mixed Models Analysis
p-value: 0.595% CI: [-0.1, 0.2]Mixed Models Analysis
Secondary
Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1
The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 1. Change from baseline in peak FEV1 within 12 hours postdose on Day 1 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline.
Time frame: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | 0.34 Litre | Standard Error 0.03 |
| GSP304 20 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | 0.38 Litre | Standard Error 0.03 |
| GSP304 40 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | 0.33 Litre | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | 0.21 Litre | Standard Error 0.03 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1 | 0.38 Litre | Standard Error 0.03 |
p-value: 0.00495% CI: [0.04, 0.21]Mixed Models Analysis
p-value: <0.00195% CI: [0.08, 0.26]Mixed Models Analysis
p-value: 0.00795% CI: [0.03, 0.21]Mixed Models Analysis
p-value: <0.00195% CI: [0.08, 0.26]Mixed Models Analysis
Secondary
Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21
The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 21. Change from baseline in peak FEV1 within 12 hours postdose on Day 21 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline.
Time frame: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | 0.37 Litre | Standard Error 0.04 |
| GSP304 20 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | 0.34 Litre | Standard Error 0.04 |
| GSP304 40 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | 0.31 Litre | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | 0.20 Litre | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21 | 0.37 Litre | Standard Error 0.04 |
p-value: 0.00195% CI: [0.08, 0.28]Mixed Models Analysis
p-value: 0.00595% CI: [0.05, 0.25]Mixed Models Analysis
p-value: 0.03295% CI: [0.01, 0.21]Mixed Models Analysis
p-value: 0.00195% CI: [0.07, 0.27]Mixed Models Analysis
Secondary
Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1
Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1.
Time frame: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | 0.22 Litre | Standard Error 0.03 |
| GSP304 20 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | 0.24 Litre | Standard Error 0.03 |
| GSP304 40 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | 0.24 Litre | Standard Error 0.03 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | 0.10 Litre | Standard Error 0.03 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1 | 0.26 Litre | Standard Error 0.03 |
p-value: 0.00395% CI: [0.04, 0.2]Mixed Models Analysis
p-value: 0.00195% CI: [0.06, 0.22]Mixed Models Analysis
p-value: 0.00195% CI: [0.06, 0.21]Mixed Models Analysis
p-value: <0.00195% CI: [0.08, 0.23]Mixed Models Analysis
Secondary
Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21
Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 Measured Over 12 Hours on Day 21.
Time frame: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | 0.23 Litre | Standard Error 0.04 |
| GSP304 20 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | 0.17 Litre | Standard Error 0.03 |
| GSP304 40 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | 0.15 Litre | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | 0.08 Litre | Standard Error 0.04 |
| SPIRIVA RESPIMAT 5 μg | Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21 | 0.23 Litre | Standard Error 0.03 |
p-value: 0.00295% CI: [0.06, 0.24]Mixed Models Analysis
p-value: 0.06195% CI: [0, 0.18]Mixed Models Analysis
p-value: 0.1495% CI: [-0.02, 0.16]Mixed Models Analysis
p-value: 0.00295% CI: [0.06, 0.24]Mixed Models Analysis
Secondary
Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1
Descriptive statistics for tiotropium urine PK parameter - Fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1
Time frame: Day 1
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 1.386 percentage of dose | Standard Deviation 0.7683 |
| GSP304 20 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 1.681 percentage of dose | Standard Deviation 1.169 |
| GSP304 40 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 1.507 percentage of dose | Standard Deviation 1.056 |
| SPIRIVA RESPIMAT 5 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1 | 4.948 percentage of dose | Standard Deviation 4.391 |
Secondary
Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21
Descriptive statistics for tiotropium urine PK parameter-Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 3.754 percentage of dose | Standard Deviation 2.869 |
| GSP304 20 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 3.236 percentage of dose | Standard Deviation 2.3 |
| GSP304 40 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 4.026 percentage of dose | Standard Deviation 2.532 |
| SPIRIVA RESPIMAT 5 μg | Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 | 15.51 percentage of dose | Standard Deviation 9.161 |
Secondary
Peak Concentrations During the Dosing Interval (Cmax) on Day 1
Descriptive statistics for tiotropium plasma PK parameters - (Cmax) on Day 1
Time frame: Day 1
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSP304 10 μg | Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | 2.632 pg/mL | Standard Deviation 1.69 |
| GSP304 20 μg | Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | 7.119 pg/mL | Standard Deviation 7.368 |
| GSP304 40 μg | Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | 14.06 pg/mL | Standard Deviation 11.98 |
| SPIRIVA RESPIMAT 5 μg | Peak Concentrations During the Dosing Interval (Cmax) on Day 1 | 10.25 pg/mL | Standard Deviation 7.944 |
Secondary
Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1
Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 1
Time frame: Day 1
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSP304 10 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | 0.067 hour |
| GSP304 20 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | 0.100 hour |
| GSP304 40 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | 0.108 hour |
| SPIRIVA RESPIMAT 5 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1 | 0.100 hour |
Secondary
Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21
Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 21
Time frame: Day 21
Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSP304 10 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | 0.075 hour |
| GSP304 20 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | 0.150 hour |
| GSP304 40 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | 0.108 hour |
| SPIRIVA RESPIMAT 5 μg | Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21 | 0.100 hour |