Healthy Subjects
Conditions
Brief summary
Demonstrate bioequivalence of guaifenesin in Mucinex® extended release (ER) 600 mg tablet in normal healthy volunteers compared to the immediate release guaifenesin 200 mg tablet reference product marketed
Interventions
DRUGMucinex®
Mucinex® 600 mg single dose ER bi-layer tablet
Sponsors
Reckitt Benckiser Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
2-Way Crossover
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent has been obtained (i.e. be informed of the nature of the study and give written consent prior to any study procedure). Able to read, understand, and sign the informed consent, after the nature of the study has been explained. 2. Age: 18 to 55 years of age, inclusive. 3. Sex: Male or female. 4. Status: Healthy subjects. 5. BMI: ≥18.0 and ≤28.0 kg/m2. 6. No clinically significant findings in vital signs measurements at screening. 7. No clinically significant abnormal laboratory values at screening. 8. No clinically significant findings from a 12-lead electrocardiogram (ECG) at screening. 9. Have no significant diseases or clinically relevant medical condition in the opinion of the investigator. 10. Males who participate in this study are willing to: * remain abstinent \[not engage in sexual intercourse\] from the start of drug administration until 90 days after the end of the study or * use (or their partner will use, as applicable) two effective methods of birth control \[condom, diaphragm, cervical cap, vaginal sponge, spermicide, IUD, tubal ligation, vasectomy, or hormonal contraceptives\] from the start of drug administration until 90 days after the end of the study. Females who participate in this study are: * unable to have children (e.g., post-menopausal, hysterectomy); * willing to remain abstinent \[not engage in sexual intercourse\] from 21 days prior to drug administration until 30 days after the end of the study; or * willing to use two effective methods of birth control \[condom, diaphragm, cervical cap, vaginal sponge, spermicide, non-hormonal Intrauterine Device (IUD) (in place for 3 months), tubal ligation, partner has vasectomy, hormonal contraceptives for 3 months prior to drug administration\] from 30 days prior to drug administration until 30 days after the end of the study. 11. Have no clinically significant findings from a physical examination.
Exclusion criteria
Subjects to whom any of the following conditions apply must be excluded: 1. Employee of Pharma Medica Research Inc. (PMRI) or Reckitt Benckiser. 2. Partner or first-degree relative of any Investigator at PMRI. 3. Known history or presence of any clinically significant medical condition. 4. Known or suspected carcinoma. 5. Presence of hepatic or renal dysfunction. 6. Presence of clinically significant gastrointestinal disease or history of malabsorption within the last year. 7. Known history or presence of galactose or fructose intolerance, sucrase-isomaltase insufficiency, Lapp lactase insufficiency, galactosemia, or glucose-galactose malabsorption syndrome. 8. Presence of a medical condition requiring regular medication (prescription and/or over-the-counter) with systemic absorption. 9. History of drug or alcohol or medicinal product addiction requiring treatment within the past two years or excessive alcohol consumption (more than 10 units per week) Note: one unit is defined as 5 ounces of wine, 12 ounces of beer, or 1.5 ounces of spirits 10. Positive test result for serum Human Chorionic Gonadotropin (hCG) consistent with pregnancy (females only), HIV, Hepatitis B surface antigen or Hepatitis C antibody. 11. Positive test result for urine drugs of abuse (cannabinoids, opiates, amphetamines, cocaine, phencyclidine, tricyclic antidepressants, barbiturates, methadone and benzodiazepines) or urine cotinine. 12. Difficulty fasting or consuming standard meals. 13. Females who are lactating. 14. Does not tolerate venipuncture. 15. Use of tobacco or nicotine-containing products within 12 months prior to drug administration. 16. On a special diet within 30 days prior to drug administration (e.g., liquid, protein, raw, food diet). 17. Donation or loss of whole blood (including clinical trials): * ≥50 ml and ≤499 ml within 30 days prior to drug administration * ≥500 ml within 56 days prior to drug administration. 18. Females who have started taking hormonal contraceptives or have changed their method or brand of hormonal birth control within 3 months prior to drug administration. 19. Have had a tattoo or body piercing within 30 days prior to drug administration. 20. Use of drugs of the monoamine oxidase inhibitor (MAOI) class within 30 days prior to drug administration. 21. Known history or presence of hypersensitivity, intolerance or idiosyncratic reaction to guaifenesin or any other drug substances with similar activity. 22. Previously enrolled in this study. 23. Participated in another clinical trial or received an investigational product within 30 days prior to drug administration. 24. Unable in the opinion of the Investigator to comply fully with the study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | Maximum measured analyte concentration over the sampling period. |
| Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUCt) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | The area under the analyte concentration versus time curve, from time zero (0) to the time of the last measurable analyte concentration (t), as calculated by the linear trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | Elimination rate constant calculated from the slope of the terminal portion of the plasma profile calculated by least squares regression of log (concentration) versus time |
| Terminal Elimination Half-life (T½) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | Terminal elimination half-life, calculated from the equation: T½ = In(2)/Kel. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | Time of the maximum measured analyte concentration over the sampling period. |
| Number of Adverse Events(AEs) Experienced by Participants | Up to period 2 (8.3 days/200 hours) | Intensity determination Mild=AE does not limit usual activities; subject may experience slight discomfort Moderate=AE results in some limitation of usual activities;subject may experience significant discomfort Severe=AE results in an inability to carry out usual activities; subject may experience intolerable discomfort or pain Unassessable/Unclassifiable=Insufficient information to be able to make an assessment Conditional/Unclassified=Insufficient information to make an assessment at present (causality is conditional on additional information) Unrelated=No possibility that the AE was caused by study drug Unlikely=Slight, but remote, chance that the AE was caused by study drug, but the balance of judgment is that it was most likely not due to the study drug Possible=Reasonable suspicion that the AE was caused by the study drug Probable=Most likely that the AE was caused by study drug Certain=The AE was definitely caused by study drug Investigational Medicinal Product (IMP) |
| Relative Bioavailability (RF) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | RF is measured by (AUCinf ER / AUCinf IR) x (ER dose / IR dose) |
| Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) of Guaifenesin | 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours | AUCinf = AUCt + Cp/Kel, where Cp is the predicted analyte concentration at the time of the last measurable analyte concentration. |
Participant flow
Recruitment details
This was a single-centre study conducted in Canada.
Pre-assignment details
Total Thirty (30) subjects were enrolled in the study among them 27 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Treatment A : Mucinex® ER 600 mg bi-layer single dose tablet by mouth under fasting condition.
Treatment B : Guaifenesin 200 mg immediate release (IR) tablet q4h (total of 3 doses) by mouth under fasting condition.
Cohort 1
Period 1 - Treatment A or Treatment B at Sequence AB.
Period 2 - Treatment B or Treatment A at Sequence BA.
Scheduled Washout of 7 days between drug administrations.
Cohort 2
Period 1 - Treatment A or Treatment B at Sequence AB.
Period 2 - Treatment B or Treatment A at Sequence BA.
Scheduled Washout of 7 days between drug administrations. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 0 | 1 |
| Period 1 | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 11 |
| Age Group 18 to 40 years | 14 Participants |
| Age Group 41 to 64 years | 16 Participants |
| Body Mass Index | 23.9 kg/m² STANDARD_DEVIATION 2.2 |
| Height | 167.4 cm STANDARD_DEVIATION 9.1 |
| Race Asian | 5 participants |
| Race Black or African American | 6 participants |
| Race White | 19 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 15 Participants |
| Weight | 67.2 kg STANDARD_DEVIATION 9.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 29 |
| other Total, other adverse events | 1 / 28 | 4 / 29 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUCt) of Guaifenesin
The area under the analyte concentration versus time curve, from time zero (0) to the time of the last measurable analyte concentration (t), as calculated by the linear trapezoidal method.
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: PK Dataset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUCt) of Guaifenesin | 4288.30 ng·h/ml | Standard Deviation 1654.57 |
| Reference: Guaifenesin 200 mg | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUCt) of Guaifenesin | 4641.48 ng·h/ml | Standard Deviation 2211.99 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Guaifenesin
Maximum measured analyte concentration over the sampling period.
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: Pharmacokinetic (PK) Parameter Set Population includes all subjects from the PK dataset with evaluable PK parameters for each treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 1076.37 ng/ml | Standard Deviation 414.8 |
| Reference: Guaifenesin 200 mg | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 1223.89 ng/ml | Standard Deviation 522.04 |
Secondary
Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) of Guaifenesin
AUCinf = AUCt + Cp/Kel, where Cp is the predicted analyte concentration at the time of the last measurable analyte concentration.
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: PK Dataset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) of Guaifenesin | 4306.21 ng·h/ml | Standard Deviation 1658.06 |
| Reference: Guaifenesin 200 mg | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) of Guaifenesin | 4647.47 ng·h/ml | Standard Deviation 2212.37 |
Secondary
Number of Adverse Events(AEs) Experienced by Participants
Intensity determination Mild=AE does not limit usual activities; subject may experience slight discomfort Moderate=AE results in some limitation of usual activities;subject may experience significant discomfort Severe=AE results in an inability to carry out usual activities; subject may experience intolerable discomfort or pain Unassessable/Unclassifiable=Insufficient information to be able to make an assessment Conditional/Unclassified=Insufficient information to make an assessment at present (causality is conditional on additional information) Unrelated=No possibility that the AE was caused by study drug Unlikely=Slight, but remote, chance that the AE was caused by study drug, but the balance of judgment is that it was most likely not due to the study drug Possible=Reasonable suspicion that the AE was caused by the study drug Probable=Most likely that the AE was caused by study drug Certain=The AE was definitely caused by study drug Investigational Medicinal Product (IMP)
Time frame: Up to period 2 (8.3 days/200 hours)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Mild | 1 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Moderate | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Severe | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unassessable/Unclassifiable | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Conditional /Unclassified | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unrelated | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unlikely | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Possible | 1 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Probable | 0 Events |
| Test: RB Mucinex® ER 600 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Certain | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Possible | 6 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Mild | 9 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unrelated | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Moderate | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Certain | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Severe | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unlikely | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Unassessable/Unclassifiable | 3 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Probable | 0 Events |
| Reference: Guaifenesin 200 mg | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP: Conditional /Unclassified | 0 Events |
Secondary
Relative Bioavailability (RF) of Guaifenesin
RF is measured by (AUCinf ER / AUCinf IR) x (ER dose / IR dose)
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: Outcome involved analyzing data from both intervention groups (ER and IR) in combination as per the provided formula, therefore, separate analysis for each intervention cannot be reported
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Relative Bioavailability (RF) of Guaifenesin | 0.9542 ng·h/ml | Standard Deviation 0.177 |
Secondary
Terminal Elimination Half-life (T½) of Guaifenesin
Terminal elimination half-life, calculated from the equation: T½ = In(2)/Kel.
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: PK Dataset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Terminal Elimination Half-life (T½) of Guaifenesin | 1.70 h | Standard Deviation 0.75 |
| Reference: Guaifenesin 200 mg | Terminal Elimination Half-life (T½) of Guaifenesin | 0.93 h | Standard Deviation 0.15 |
Secondary
Terminal Elimination Rate Constant (Kel) of Guaifenesin
Elimination rate constant calculated from the slope of the terminal portion of the plasma profile calculated by least squares regression of log (concentration) versus time
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: PK Dataset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.4727 1/h | Standard Deviation 0.1711 |
| Reference: Guaifenesin 200 mg | Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.7635 1/h | Standard Deviation 0.1011 |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Guaifenesin
Time of the maximum measured analyte concentration over the sampling period.
Time frame: 0 (pre-dose) ,0.25,0.5, 0.75, 1,1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 20 and 24 hours
Population: PK Dataset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test: RB Mucinex® ER 600 mg | Time to Maximum Observed Plasma Concentration (Tmax) of Guaifenesin | 0.75 hr | Standard Deviation 0.33 |
| Reference: Guaifenesin 200 mg | Time to Maximum Observed Plasma Concentration (Tmax) of Guaifenesin | 1.45 hr | Standard Deviation 2.43 |