Healthy Volunteers
Conditions
Keywords
Bioequivalence, Healthy Volunteers
Brief summary
This is a bioequivalence trial to evaluate the bioequivalence of Myrin P Forte against reference drug in healthy volunteers.
Interventions
DRUGMyrin P Forte
Tablet containing Rifampicin, Isoniazid, Ethambutol and Pyrazinamide, given once daily, single dose
DRUGSingle drug references
containing Rifampicin, Isoniazid, Ethambutol and Pyrazinamide as single agents
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, male or female, 21 to 55 years of age, body weight no less than 55 kg, Body mass index (BMI) of 17.5 to 30.5 kg/m2. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead electrocardiogram (ECG) or clinical laboratory tests. * An informed consent document signed and dated by the subject. * Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), positive Hepatitis B surface antigen or Human Immunodeficiency Virus (HIV) serology results. * pregnant or nursing female, * alcohol, drug, smoke user, * sensitive to any study medication or related component, * History or active gout, * History or active tuberculosis, * Known optic neuritis or other ophthalmological conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose | It is obtained from Cmax divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours (hrs) post-dose | Area under the plasma concentration-time curve from time zero (pre-dose) to the time of last measured concentration (AUClast). |
| Maximum Observed Plasma Concentration (Cmax) | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose | — |
| Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose | AUClast\[dn\] = Dose normalized area under the plasma concentration-time curve (AUC\[dn\]) from time zero (pre-dose) to the time of last measured concentration. It is obtained from AUClast divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose | 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-∞). |
| Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose | AUC \[0-∞\]\[dn\] = Dose normalized area under the plasma concentration versus time curve (AUC\[dn\]) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-∞) divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion. |
| Plasma Decay Half-life (t1/2) | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide | — |
Countries
Singapore
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes participants randomized to receive Myrin-P Forte first and four single drug references first. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 32.6 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 36 | 31 / 35 |
| serious Total, serious adverse events | 0 / 36 | 0 / 35 |
Outcome results
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the plasma concentration-time curve from time zero (pre-dose) to the time of last measured concentration (AUClast).
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours (hrs) post-dose
Population: Pharmacokinetic (PK) parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Myrin-P Forte | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Rifampicin | 79360.0 ng*hr/mL | Standard Deviation 29613 |
| Myrin-P Forte | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Isoniazid | 20550.0 ng*hr/mL | Standard Deviation 12920 |
| Myrin-P Forte | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Ethambutol | 15070.0 ng*hr/mL | Standard Deviation 3298.8 |
| Four Single Drug References | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Rifampicin | 77180.0 ng*hr/mL | Standard Deviation 20516 |
| Four Single Drug References | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Isoniazid | 18800.0 ng*hr/mL | Standard Deviation 12941 |
| Four Single Drug References | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Ethambutol | 15170.0 ng*hr/mL | Standard Deviation 3119.1 |
Comparison: Rifampicin; 32 participants (16 per sequence) provided at least 99% power that 90% confidence interval (CI) for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject coefficient of variation (CV) estimate of approximately 14.5% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [99.2, 108.64]
Comparison: Isoniazid; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 12.0% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [101.95, 112.9]
Comparison: Ethambutol; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 12.9% for AUClast was used for this power calculation. Natural log transformed AUClast was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [94.92, 104.25]
Primary
Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide
AUClast\[dn\] = Dose normalized area under the plasma concentration-time curve (AUC\[dn\]) from time zero (pre-dose) to the time of last measured concentration. It is obtained from AUClast divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin-P Forte | Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide | 453500 (ng*hr/mL)/mg | Standard Deviation 76250 |
| Four Single Drug References | Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) for Pyrazinamide | 447900 (ng*hr/mL)/mg | Standard Deviation 82578 |
Comparison: Pyrazinamide; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for AUClast lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 5.2% for AUClast was used for this power calculation. Natural log transformed AUClast(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [99.12, 104.4]
Primary
Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide
It is obtained from Cmax divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin-P Forte | Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide | 33890.0 (ng/mL)/mg | Standard Deviation 6490.2 |
| Four Single Drug References | Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) for Pyrazinamide | 35580.0 (ng/mL)/mg | Standard Deviation 12134 |
Comparison: Pyrazinamide; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 6.7% for Cmax was used for this power calculation. Natural log transformed Cmax(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [88.6, 102.22]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Myrin-P Forte | Maximum Observed Plasma Concentration (Cmax) | Isoniazid | 4418.0 ng/mL | Standard Deviation 1619 |
| Myrin-P Forte | Maximum Observed Plasma Concentration (Cmax) | Rifampicin | 12120.0 ng/mL | Standard Deviation 3682.3 |
| Myrin-P Forte | Maximum Observed Plasma Concentration (Cmax) | Ethambutol | 2771.0 ng/mL | Standard Deviation 825.4 |
| Four Single Drug References | Maximum Observed Plasma Concentration (Cmax) | Rifampicin | 11830.0 ng/mL | Standard Deviation 2351.8 |
| Four Single Drug References | Maximum Observed Plasma Concentration (Cmax) | Isoniazid | 4237.0 ng/mL | Standard Deviation 1658.9 |
| Four Single Drug References | Maximum Observed Plasma Concentration (Cmax) | Ethambutol | 2865.0 ng/mL | Standard Deviation 950.5 |
Comparison: Rifampicin: 32 participants (16 per sequence) provided at least 98% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 18.2% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [95.36, 110.71]
Comparison: Isoniazid; 32 participants (16 per sequence) provided at least 98% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 18.2% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [92.13, 117.07]
Comparison: Ethambutol; 32 participants (16 per sequence) provided at least 99% power that 90% CI for ratio of test to reference for Cmax lie within acceptance region of 80% - 125%. An intra-subject CV estimate of approximately 16.0% for Cmax was used for this power calculation. Natural log transformed Cmax was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [94.92, 104.25]
Secondary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞])
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-∞).
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period. Here, 'n' is number of participants who were evaluable for this measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Myrin-P Forte | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Rifampicin (n= 36, 35) | 80940.0 ng*hr/mL | Standard Deviation 34613 |
| Myrin-P Forte | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Isoniazid (n= 35, 35) | 21210.0 ng*hr/mL | Standard Deviation 13562 |
| Myrin-P Forte | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Ethambutol (n= 28, 31) | 17150.0 ng*hr/mL | Standard Deviation 3362.1 |
| Four Single Drug References | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Rifampicin (n= 36, 35) | 78400.0 ng*hr/mL | Standard Deviation 22226 |
| Four Single Drug References | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Isoniazid (n= 35, 35) | 19460.0 ng*hr/mL | Standard Deviation 14171 |
| Four Single Drug References | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-∞]) | Ethambutol (n= 28, 31) | 17050.0 ng*hr/mL | Standard Deviation 3378.9 |
Comparison: Rifampicin; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [99.7, 109.1]
Comparison: Isoniazid; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [100.32, 111.46]
Comparison: Ethambutol; Natural log transformed AUC(0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [96.28, 105.88]
Secondary
Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide
AUC \[0-∞\]\[dn\] = Dose normalized area under the plasma concentration versus time curve (AUC\[dn\]) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-∞) divided by dose and then multiplied by 1500. The test and reference for pyrazinamide were given at different doses, so dose-normalized parameters were used for analysis for adjusting the dose effect on bioequivalence conclusion.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin-P Forte | Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide | 471000 (ng*hr/mL)/mg | Standard Deviation 85153 |
| Four Single Drug References | Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞][dn]) for Pyrazinamide | 464800 (ng*hr/mL)/mg | Standard Deviation 92222 |
Comparison: Pyrazinamide; Natural log transformed AUC (0 -∞)(dn) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect.90% CI: [99.24, 104.43]
Secondary
Plasma Decay Half-life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period. Here, 'n' is number of participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Myrin-P Forte | Plasma Decay Half-life (t1/2) | Rifampicin (n= 36, 35) | 3.6630 hr | Standard Deviation 1.0477 |
| Myrin-P Forte | Plasma Decay Half-life (t1/2) | Isoniazid (n= 35, 35) | 3.7340 hr | Standard Deviation 0.9197 |
| Myrin-P Forte | Plasma Decay Half-life (t1/2) | Ethambutol (n= 28, 31) | 7.7430 hr | Standard Deviation 1.1716 |
| Myrin-P Forte | Plasma Decay Half-life (t1/2) | Pyrazinamide (n= 36, 35) | 9.8630 hr | Standard Deviation 1.3333 |
| Four Single Drug References | Plasma Decay Half-life (t1/2) | Pyrazinamide (n= 36, 35) | 9.7660 hr | Standard Deviation 1.3671 |
| Four Single Drug References | Plasma Decay Half-life (t1/2) | Rifampicin (n= 36, 35) | 3.4290 hr | Standard Deviation 0.6938 |
| Four Single Drug References | Plasma Decay Half-life (t1/2) | Ethambutol (n= 28, 31) | 7.6390 hr | Standard Deviation 1.1158 |
| Four Single Drug References | Plasma Decay Half-life (t1/2) | Isoniazid (n= 35, 35) | 3.9470 hr | Standard Deviation 1.1751 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hrs post-dose for rifampicin, isoniazid and ethambutol and additional 36 and 48 hrs post-dose for pyrazinamide
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters for one of four analytes in at least 1 treatment period.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Myrin-P Forte | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Rifampicin | 2.00 hr |
| Myrin-P Forte | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Isoniazid | 1.02 hr |
| Myrin-P Forte | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Ethambutol | 2.77 hr |
| Myrin-P Forte | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Pyrazinamide | 1.50 hr |
| Four Single Drug References | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Pyrazinamide | 1.50 hr |
| Four Single Drug References | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Rifampicin | 1.50 hr |
| Four Single Drug References | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Ethambutol | 2.48 hr |
| Four Single Drug References | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Isoniazid | 1.00 hr |