Tuberculosis
Conditions
Keywords
bioequivalence; rifampicin
Brief summary
This study is done to demonstrate bioequivalence of rifampicin component in Myrin© 2 Fixed-Dose Combination Tablet (each contains 75 mg isoniazid and 150 mg rifampicin, Pfizer Inc) with equivalent dose of the reference Rimactane® capsule (each contains 300 mg rifampicin, Novartis Sandoz) in healthy Filipino male subjects. This study also aims to determine the safety and tolerability of Myrin© 2 tablets and Rimactane® capsules in these subjects.
Interventions
DRUGMyrin© 2 (Rifampicin + Isoniazid)
Two (2) fixed-dose combination tablets each containing Rifampicin 150 mg and Isoniazid 75 mg
DRUGRimactane® (Rifampicin)
One (1) capsule of Rifampicin 300 mg
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects between the ages of 18 and 55 years, inclusive. * Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lbs). * An informed consent document signed and dated by the subject. * Subjects willing and able to comply with 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, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * Any condition possibly affecting drug absorption (e.g., gastrectomy). * A positive urine drug screen. * History of regular alcohol consumption exceeding 21 drinks/week (1 drink = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of hard liquor) within 6 months of screening. * Treatment with an investigational drug within 3 months (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication. * 12-lead ECG demonstrating QTc \>450 msec at screening. If QTc exceeds 450 msec, the ECG should be repeated two more times and the average of the three QTc values should be used to determine the subject's eligibility. * History of previous treatment for TB or is suspected of suffering from TB. * Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Herbal medication, herbal supplements and hormone replacement therapy must be discontinued 28 days prior to the first dose of study medication. As an exception, acetaminophen / paracetamol may be used at doses of less than 1 g/day. Limited use of non-prescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case-by-case basis following approval by the sponsor. * Blood donation of approximately 1 pint (500 ml) within 56 days prior to dosing. * A history of hypersensitivity to any of the study medications or related substances, or to any of the ingredients used in the study drug formulations. * Unwilling or unable to comply with the Lifestyle guidelines described in this protocol. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. * Recent history of diarrhea (2 weeks). * Recent use of oral (2 weeks) or IV (2-3 months) antibiotics to assure normal bowel flora at study start.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC [0-t]) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hours (hrs) post-dose | AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) |
| Maximum Observed Plasma Concentration (Cmax) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose | — |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 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-∞). |
| Plasma Decay Half-life (t1/2) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose | AUC%extrapolated is the extrapolated area under the plasma concentration time profile following the last measured concentration. It is calculated as (AUC \[0-∞\] minus AUC\[0-10\])\*100/ AUC (0-∞), where AUC (0-∞) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-10) = area under the plasma concentration time-curve from zero (pre-dose) to the last quantifiable concentration. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinically Significant Change From Baseline Pulse Rate | Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline) | Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline. |
| Number of Participants With Abnormal Safety Laboratory Test Values | Screening and Follow-up (1 week post-baseline) | Participants were evaluated for following safety laboratory tests: Hematology, chemistry, urinalysis. |
| Clinically Significant Change From Baseline Supine Blood Pressure (BP) | Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline) | Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline. |
| Clinically Significant Change From Baseline Oral Temperature | Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline) | Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline. |
| Clinically Significant Change From Baseline Respiratory Rate | Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline) | Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline. |
| Number of Participants With Adverse Events (AEs) | Baseline (Day 0), Day 1 and Follow-up (1 week post-baseline) | Any untoward medical occurrence in a participant who received study treatment was considered an AE without regard to possibility of causal relationship. |
Countries
Philippines
Participant flow
Pre-assignment details
Out of 22 participants enrolled, only 21 participants were randomized since 1 participant withdrew from the study.
Participants by arm
| Arm | Count |
|---|---|
| Participants Eligible for Analysis Includes participants randomized to receive Myrin 2 first and Rimactane first and who had completed the study. It excludes 1 participant who did not meet the weight requirement for the study (protocol violator). | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Participants Eligible for Analysis |
|---|---|
| Age, Customized 18 to 22 years | 12 participants |
| Age, Customized 23 to 27 years | 4 participants |
| Age, Customized 28 to 32 years | 2 participants |
| Age, Customized 33 to 37 years | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 21 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 |
Outcome results
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC [0-t])
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: 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hours (hrs) post-dose
Population: Pharmacokinetic (PK) parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin 2 | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC [0-t]) | 38.59 microgram*hour/milliliter (mcg*h/mL) | Geometric Coefficient of Variation 24.99 |
| Rimactane | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC [0-t]) | 38.81 microgram*hour/milliliter (mcg*h/mL) | Geometric Coefficient of Variation 21.95 |
Comparison: 20 participants (10 per sequence) provided at least 98% power that 90% confidence interval (CI) for ratio of test to reference for AUC(0-t) of rifampicin lie within acceptance region of 80%-125%. Intra-participant coefficient of variation (CV) estimate of approximately 13.48% for AUC(0-t) was used for this power calculation. Natural log transformed AUC(0-t) was analyzed using mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as random effect.90% CI: [92.98, 105.2]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose
Population: PK parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin 2 | Maximum Observed Plasma Concentration (Cmax) | 7.89 mcg/mL | Geometric Coefficient of Variation 24.89 |
| Rimactane | Maximum Observed Plasma Concentration (Cmax) | 8.02 mcg/mL | Geometric Coefficient of Variation 22.35 |
Comparison: 20 participants (10 per sequence) provided at least 94% power that 90% CI for ratio of test to reference for Cmax of rifampicin lie within acceptance region of 80%-125%. Intra-participant CV estimate of approximately 16.43% 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 random effect.90% CI: [87.77, 109.97]
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), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose
Population: PK parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin 2 | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 47.72 mcg*hr/mL | Geometric Coefficient of Variation 30.54 |
| Rimactane | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 47.15 mcg*hr/mL | Geometric Coefficient of Variation 25.32 |
Comparison: Natural log transformed AUC(0-∞) of rifampicin 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: [94.44, 106.41]
Secondary
Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated)
AUC%extrapolated is the extrapolated area under the plasma concentration time profile following the last measured concentration. It is calculated as (AUC \[0-∞\] minus AUC\[0-10\])\*100/ AUC (0-∞), where AUC (0-∞) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-10) = area under the plasma concentration time-curve from zero (pre-dose) to the last quantifiable concentration.
Time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose
Population: PK parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Myrin 2 | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 18.84 Percent AUC | Geometric Coefficient of Variation 38.47 |
| Rimactane | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 17.53 Percent AUC | Geometric Coefficient of Variation 30.23 |
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), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose
Population: PK parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Myrin 2 | Plasma Decay Half-life (t1/2) | 4.0750 hrs | Standard Deviation 1.0777 |
| Rimactane | Plasma Decay Half-life (t1/2) | 3.8635 hrs | Standard Deviation 0.8347 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8 and 10 hrs post-dose
Population: PK parameter analysis population included all enrolled and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Myrin 2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2.0 hrs |
| Rimactane | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 1.0 hrs |
Other Pre-specified
Clinically Significant Change From Baseline Oral Temperature
Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline.
Time frame: Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline)
Population: Data was not summarized since oral temperature remained within normal limits throughout the study and there were no significant deviations from baseline.
Other Pre-specified
Clinically Significant Change From Baseline Pulse Rate
Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline.
Time frame: Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline)
Population: Data was not summarized since pulse rate remained within normal limits throughout the study and there were no significant deviations from baseline.
Other Pre-specified
Clinically Significant Change From Baseline Respiratory Rate
Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline.
Time frame: Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline)
Population: Data was not summarized since respiratory rate remained within normal limits throughout the study and there were no significant deviations from baseline.
Other Pre-specified
Clinically Significant Change From Baseline Supine Blood Pressure (BP)
Mean change: vital sign value at observation (Day 1 and follow-up) minus vital sign value at baseline.
Time frame: Baseline (Day 0), Day 1 (Hour 10), and follow-up (1 week post-baseline)
Population: Data was not summarized since supine systolic and diastolic BP remained within normal limits throughout the study and there were no significant deviations from baseline.
Other Pre-specified
Number of Participants With Abnormal Safety Laboratory Test Values
Participants were evaluated for following safety laboratory tests: Hematology, chemistry, urinalysis.
Time frame: Screening and Follow-up (1 week post-baseline)
Population: Safety population included participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myrin 2 | Number of Participants With Abnormal Safety Laboratory Test Values | Screening | 0 participants |
| Myrin 2 | Number of Participants With Abnormal Safety Laboratory Test Values | Follow-up | 0 participants |
| Rimactane | Number of Participants With Abnormal Safety Laboratory Test Values | Screening | 0 participants |
| Rimactane | Number of Participants With Abnormal Safety Laboratory Test Values | Follow-up | 0 participants |
Other Pre-specified
Number of Participants With Adverse Events (AEs)
Any untoward medical occurrence in a participant who received study treatment was considered an AE without regard to possibility of causal relationship.
Time frame: Baseline (Day 0), Day 1 and Follow-up (1 week post-baseline)
Population: Safety population included participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myrin 2 | Number of Participants With Adverse Events (AEs) | Day 0 | 0 participants |
| Myrin 2 | Number of Participants With Adverse Events (AEs) | Day 1 | 0 participants |
| Myrin 2 | Number of Participants With Adverse Events (AEs) | Follow-up | 0 participants |
| Rimactane | Number of Participants With Adverse Events (AEs) | Day 0 | 0 participants |
| Rimactane | Number of Participants With Adverse Events (AEs) | Day 1 | 0 participants |
| Rimactane | Number of Participants With Adverse Events (AEs) | Follow-up | 0 participants |