Healthy Volunteers
Conditions
Keywords
Bioequivalence, RIN 150, Healthy volunteers
Brief summary
This is a bioequivalence study to evaluate the bioequivalence of RIN 150 against individual reference drugs in healthy volunteers.
Interventions
DRUGRIN 150
Each subject will receive a single oral dose of 4 fixed dose combination tablets (RIN 150) each contains 150 rifampicin and 75 mg isoniazid.
DRUGreference drugs
Each subject will receive a single oral dose of 4 x 150 mg rifampicin capsules and 3 x 100 mg isoniazid capsules.
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, with a signed and dated informed consent document and is 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 HIV serology results; * Pregnant or nursing female; * History or active tuberculosis; * Participated in investigational drug studies within 3 months; * Used prescription or nonprescription drugs within 7 days or 5 half-lives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) was reported for rifampicin and isoniazid. |
| Maximum Observed Plasma Concentration (Cmax) | 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1 | Cmax was reported for rifampicin and isoniazid. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1 | Tmax was reported for rifampicin and isoniazid. |
| Plasma Decay Half-Life (t1/2) | 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1 | Plasma decay half life (t1/2) was reported for rifampicin and isoniazid. |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours 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 - ∞) was reported for rifampicin and isoniazid. It is obtained from AUC (0 - t) plus AUC (t - ∞). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes in Vital Signs | Screening up to Day 2 of intervention period 2 | Criteria for clinical significant change in vital signs: systolic blood pressure (BP) less than (\<) 90 millimeters of mercury (mmHg), diastolic BP \<50 mmHg, supine and sitting heart rate \<40 beats per minute (bpm) or greater than (\>) 120 bpm, standing and erect heart rate \<40 bpm or \>140 bpm. Maximum change from baseline in systolic BP \>=30 mmHg, maximum change from baseline in diastolic BP \>=20 mmHg. Participants who met the criteria were reported. |
| Number of Participants With Laboratory Test Abnormalities | Screening up to Day 2 of intervention period 2 | Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (less than \[\<\] 0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6/ greater than \[\>\] 1.5\*limit of reference range \[LRR\]); platelets (\<0.5/\>1.75\*LRR); neutrophils, lymphocytes (\<0.8/\>1.2\*LRR); eosinophils, basophils, monocytes (\>1.2\*upper LN \[ULN\]); bilirubin (\>1.5\*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\*ULN); creatinine, urea (\>1.3\*ULN); fasting glucose (\<0.6 /\>1.5\*LRR); uric acid (\>1.2\*ULN); sodium (\<0.95/\>1.05\*LRR); potassium, calcium, chloride, bicarbonate (\<0.9/\>1.1\*LRR); albumin, total protein (\<0.8/\>1.2\*LRR); creatine kinase (\>2.0\*ULN); urine red blood cells (RBCs), urine white blood cells (WBCs) (\>=20 high-powered field). Total number of participants with any laboratory abnormalities was reported. |
Countries
Singapore
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all participants randomized to receive RIN 150 first and rifampicin and isoniazid first. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention Period 1 | Adverse Event | 0 | 1 |
| Intervention Period 1 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 7.1 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 27 | 26 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) was reported for rifampicin and isoniazid.
Time frame: 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Population: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| RIN 150 | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | AUClast: Rifampicin | 85020 (nanogram*hour) per milliliter (ng*h/mL) | Geometric Coefficient of Variation 20 |
| RIN 150 | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | AUClast: Isoniazid | 16220 (nanogram*hour) per milliliter (ng*h/mL) | Geometric Coefficient of Variation 79 |
| Rifampicin and Isoniazid | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | AUClast: Rifampicin | 90030 (nanogram*hour) per milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
| Rifampicin and Isoniazid | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | AUClast: Isoniazid | 16120 (nanogram*hour) per milliliter (ng*h/mL) | Geometric Coefficient of Variation 77 |
Comparison: Natural log transformed AUClast of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [92.07, 98.94]
Comparison: Natural log transformed AUClast of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [99.33, 107.75]
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax was reported for rifampicin and isoniazid.
Time frame: 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Population: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| RIN 150 | Maximum Observed Plasma Concentration (Cmax) | Cmax: Rifampicin | 13670 ng/mL | Geometric Coefficient of Variation 21 |
| RIN 150 | Maximum Observed Plasma Concentration (Cmax) | Cmax: Isoniazid | 6080 ng/mL | Geometric Coefficient of Variation 45 |
| Rifampicin and Isoniazid | Maximum Observed Plasma Concentration (Cmax) | Cmax: Rifampicin | 15000 ng/mL | Geometric Coefficient of Variation 28 |
| Rifampicin and Isoniazid | Maximum Observed Plasma Concentration (Cmax) | Cmax: Isoniazid | 5577 ng/mL | Geometric Coefficient of Variation 37 |
Comparison: Natural log transformed Cmax of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [83.13, 101.01]
Comparison: Natural log transformed Cmax of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [96.07, 120.47]
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 - ∞) was reported for rifampicin and isoniazid. It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time frame: 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Population: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest. Here, n=participants in the treatment group who were evaluable for this measure for specified drug of each group with reportable AUC (0 - ∞) values, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| RIN 150 | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞): Rifampicin (n=27, 27) | 86670 ng*h/mL | Geometric Coefficient of Variation 21 |
| RIN 150 | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞): Isoniazid (n=27, 26) | 16680 ng*h/mL | Geometric Coefficient of Variation 78 |
| Rifampicin and Isoniazid | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞): Rifampicin (n=27, 27) | 91340 ng*h/mL | Geometric Coefficient of Variation 24 |
| Rifampicin and Isoniazid | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞): Isoniazid (n=27, 26) | 17390 ng*h/mL | Geometric Coefficient of Variation 71 |
Comparison: Natural log transformed AUC(0 - ∞) of rifampicin was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [92.54, 99.43]
Comparison: Natural log transformed AUC(0 - ∞) of isoniazid was analyzed using mixed effects model with sequence,period and treatment as fixed effects and participant within sequence as random effect.The adjusted mean differences and 90% confidence intervals(CIs) for the differences were exponentiated to provide estimates of ratio of adjusted geometric means(Test/Reference) and 90% CIs for the ratios,where FDC tablet were test and single drugs were reference.Values were back-transformed from the log scale.90% CI: [98.76, 106.19]
Secondary
Plasma Decay Half-Life (t1/2)
Plasma decay half life (t1/2) was reported for rifampicin and isoniazid.
Time frame: 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Population: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest. Here, n=participants in the treatment group who were evaluable for this measure for specified drug of each group with reportable t½ values, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RIN 150 | Plasma Decay Half-Life (t1/2) | t1/2: Rifampicin (n=27, 27) | 3.608 hour | Standard Deviation 0.89531 |
| RIN 150 | Plasma Decay Half-Life (t1/2) | t1/2: Isoniazid (n=27, 26) | 2.776 hour | Standard Deviation 1.411 |
| Rifampicin and Isoniazid | Plasma Decay Half-Life (t1/2) | t1/2: Rifampicin (n=27, 27) | 3.572 hour | Standard Deviation 0.72948 |
| Rifampicin and Isoniazid | Plasma Decay Half-Life (t1/2) | t1/2: Isoniazid (n=27, 26) | 3.000 hour | Standard Deviation 1.4375 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Tmax was reported for rifampicin and isoniazid.
Time frame: 0 hour (pre-dose), 0.25, 0.5, 0.75, 1, 1.33 (1 hour 20 minutes), 1.67 (1 hour 40 minutes), 2, 2.33 (2 hours 20 minutes), 2.67 (2 hours 40 minutes), 3, 3.5, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Population: Pharmacokinetic parameter analysis set included all treated participants who had at least 1 estimated pharmacokinetic parameter of primary interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RIN 150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax: Rifampicin | 1.67 hour |
| RIN 150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax: Isoniazid | 0.500 hour |
| Rifampicin and Isoniazid | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax: Isoniazid | 0.500 hour |
| Rifampicin and Isoniazid | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax: Rifampicin | 1.67 hour |
Other Pre-specified
Number of Participants With Clinically Significant Changes in Vital Signs
Criteria for clinical significant change in vital signs: systolic blood pressure (BP) less than (\<) 90 millimeters of mercury (mmHg), diastolic BP \<50 mmHg, supine and sitting heart rate \<40 beats per minute (bpm) or greater than (\>) 120 bpm, standing and erect heart rate \<40 bpm or \>140 bpm. Maximum change from baseline in systolic BP \>=30 mmHg, maximum change from baseline in diastolic BP \>=20 mmHg. Participants who met the criteria were reported.
Time frame: Screening up to Day 2 of intervention period 2
Population: Safety analysis set consisted of all participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIN 150 | Number of Participants With Clinically Significant Changes in Vital Signs | 0 participants |
| Rifampicin and Isoniazid | Number of Participants With Clinically Significant Changes in Vital Signs | 0 participants |
Other Pre-specified
Number of Participants With Laboratory Test Abnormalities
Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (less than \[\<\] 0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6/ greater than \[\>\] 1.5\*limit of reference range \[LRR\]); platelets (\<0.5/\>1.75\*LRR); neutrophils, lymphocytes (\<0.8/\>1.2\*LRR); eosinophils, basophils, monocytes (\>1.2\*upper LN \[ULN\]); bilirubin (\>1.5\*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\*ULN); creatinine, urea (\>1.3\*ULN); fasting glucose (\<0.6 /\>1.5\*LRR); uric acid (\>1.2\*ULN); sodium (\<0.95/\>1.05\*LRR); potassium, calcium, chloride, bicarbonate (\<0.9/\>1.1\*LRR); albumin, total protein (\<0.8/\>1.2\*LRR); creatine kinase (\>2.0\*ULN); urine red blood cells (RBCs), urine white blood cells (WBCs) (\>=20 high-powered field). Total number of participants with any laboratory abnormalities was reported.
Time frame: Screening up to Day 2 of intervention period 2
Population: Safety analysis set consisted of all participants who received at least 1 dose of study medication. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIN 150 | Number of Participants With Laboratory Test Abnormalities | 4 participants |
| Rifampicin and Isoniazid | Number of Participants With Laboratory Test Abnormalities | 2 participants |