Healthy Subjects
Conditions
Brief summary
Determine and compare the plasma concentrations and safety and tolerability of Guaifenesin and hydrocodone bitartrate when they are administered alone or in combination to normal healthy male and/or female subjects.
Interventions
DRUGHumibid®
Humibid® 1200 mg (single extended release) tablet
Hydrocodone Bitartrate (3.33 mg q4h X 3)
DRUGHumibid® and Hydrocodone Bitartrate tablet
Humibid® 1200 mg (single extended release) tablet and Hydrocodone bitartrate (3.33 mg q4h X 3)
Sponsors
Reckitt Benckiser LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Males and/or females between the ages of 19 and 55 years, inclusive. 2. Females of childbearing potential were using one of the following acceptable birth control methods: * Intrauterine device (IUD) in place for at least 3 months prior to study; * Barrier method (condom or diaphragm) with spermicide for at least 14 days prior to screening through 30 days beyond study completion; * Stable hormonal contraceptive for at least 3 months prior to study through 30 days beyond completion of study; Abstinence was not an acceptable form of contraception. Females of non-childbearing potential were surgically sterile (bilateral tubal ligation with surgery at least 6 months prior to study, hysterectomy, or bilateral oophorectomy at least 3 months prior to study) or postmenopausal \<2 years. An FSH \>40 mIU/mL was obtained and in the record. 3. Good general health was determined by medical history, physical examination, electrocardiogram (ECG), and clinical laboratory measures. 4. Within 15% of Ideal Body Weight as defined by the 1983 Metropolitan Life chart. 5. Non-tobacco users, who had not used nicotine or nicotine-containing products for at least 1 year. 6. Able to read, understand, and sign the informed consent after the nature of the study had been explained. 7. Negative finding on tests for Hepatitis B and C antigen as well as HIV and pregnancy test (if female). 8. Negative urine screen for drugs of abuse and alcohol at screening and the first check in. 9. Non-alcohol or drug abuser - for alcohol, defined as history of less then 4 drinks daily.
Exclusion criteria
1. Clinically significant abnormalities detected by medical history, physical, ECG, or clinical laboratory findings (as determined by the Principal Investigator). Any disease or condition which impacted absorption, distribution, metabolism, or elimination of the study drugs. 2. Females who were pregnant or nursing. 3. History of hypersensitivity reaction to the study drugs or related compounds, such as other opioids. 4. Receipt of an investigational drug within 1 month prior to study enrollment. 5. Donation of blood or significant loss of blood within 56 days or plasma within 14 days prior study enrollment. 6. Known or suspected use of illicit drugs (including codeine or hydrocodone, etc.). 7. The use of any medication on a chronic basis with the exception of oral contraceptives for women of childbearing potential. An appropriate drug-free period for prescription or over-the-counter (OTC) drugs provided to washout any especially long half-life drugs. 8. Consumption of alcohol within 48 hours prior to each dosing period. 9. Consumption of grapefruit 14 days prior to dosing and throughout the study. 10. Hemoglobin value \< 12 g/dL. If a subject's hemoglobin dropped below 11.0 g/dL the subject was dropped from the study at the Principal Investigator's discretion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | The area under the plasma concentration versus time curve from time 0 to infinity, calculated as AUC(0-t) + Ct/ Kel, where Ct is the last measurable concentration. |
| Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration) |
| Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | Pharmacokinetic Parameter AUC(0-t) The area under the plasma concentration versus time curve from time 0 to time of the last measurable concentration. |
| Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | Apparent first-order terminal elimination half-life was calculated as 0.693/Kel. |
| Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve. The parameter was calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase. |
| Time to Maximum Observed Concentration (Tmax) of Guaifenesin | 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose | Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events(AEs) Experienced by Participants | Upto Day 17 | Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities; subject may have experienced slight discomfort. Moderate = AE resulted in some limitation of usual activities; subject may have experienced significant discomfort. Severe = AE resulted in an inability to carry out usual activities; subject may have experienced intolerable discomfort/ pain. Relationship to Investigational Medicinal Products (IMP) Unlikely = Slight, but remote, chance that AE was caused by IMP. Possible = Reasonable suspicion that the AE was caused by IMP. Probable = Most likely that AE was caused by IMP. |
Participant flow
Recruitment details
This was a single-centre study.
Pre-assignment details
A total of 24 subjects entered the study, among them 23 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants were randomized at each visit to receive either
Treatment A (Reference): Single Humibid® 1200 mg guaifenesin Extended-Release (ER) bi-layer tablet by mouth under fasted state
Treatment B (Reference): Hydrocodone Bitartrate 10 mg (3.33 mg q4h X 3) tablet by mouth under fasted state
Treatment C (Test): Single Humibid® 1200 mg guaifenesin Extended-Release (ER) bi-layer tablet and Hydrocodone Bitartrate 10 mg (3.33 mg q4h X 3) tablet by mouth under fasted state
Scheduled Washout of 7 days between each doses.
All study participants received all three treatments | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Third Intervention (1 Day) | Screen failure | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 29.6 Years STANDARD_DEVIATION 9.2 |
| Elbow Breadth | 2.6 Inches STANDARD_DEVIATION 0.2 |
| Frame Size Large | 2 participants |
| Frame Size Medium | 15 participants |
| Frame Size Small | 7 participants |
| Height | 67.5 Inches STANDARD_DEVIATION 3.3 |
| Race/Ethnicity, Customized American Indian | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 17 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 148.3 lb STANDARD_DEVIATION 18.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 5 / 24 | 10 / 23 | 10 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 24 |
Outcome results
Primary
Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin
Apparent first-order terminal elimination half-life was calculated as 0.693/Kel.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin | 4.82 hr | Standard Deviation 3.3 |
| Treatment C (Test) - Plasma Guaifenesin | Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin | 5.34 hr | Standard Deviation 3.13 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin | 4.71 hr | Standard Deviation 0.833 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Apparent Terminal Elimination Half-life (T1/2) of Guaifenesin | 4.60 hr | Standard Deviation 0.831 |
Primary
Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin
Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve. The parameter was calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.205 1/hr | Standard Deviation 0.104 |
| Treatment C (Test) - Plasma Guaifenesin | Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.207 1/hr | Standard Deviation 0.199 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.151 1/hr | Standard Deviation 0.0251 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Apparent Terminal Elimination Rate Constant (Kel) of Guaifenesin | 0.155 1/hr | Standard Deviation 0.0233 |
Primary
Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin
The area under the plasma concentration versus time curve from time 0 to infinity, calculated as AUC(0-t) + Ct/ Kel, where Ct is the last measurable concentration.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin | 8501.5 ng*hr/mL | Standard Deviation 2784.5 |
| Treatment C (Test) - Plasma Guaifenesin | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin | 8347.8 ng*hr/mL | Standard Deviation 2762.4 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin | 140.44 ng*hr/mL | Standard Deviation 32.792 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Area Under Plasma Concentration-time Curve From Time 0 to Infinity (AUC(0-inf)) of Guaifenesin | 139.70 ng*hr/mL | Standard Deviation 26.044 |
Primary
Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin
Pharmacokinetic Parameter AUC(0-t) The area under the plasma concentration versus time curve from time 0 to time of the last measurable concentration.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin | 8286.2 ng*hr/mL | Standard Deviation 2440 |
| Treatment C (Test) - Plasma Guaifenesin | Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin | 8186.7 ng*hr/mL | Standard Deviation 2801 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin | 133.36 ng*hr/mL | Standard Deviation 29.407 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Area Under Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of Guaifenesin | 132.99 ng*hr/mL | Standard Deviation 23.053 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Guaifenesin
Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets included all the 24 subjects for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 1770 ng/mL | Standard Deviation 628 |
| Treatment C (Test) - Plasma Guaifenesin | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 1810 ng/mL | Standard Deviation 784 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 11.3 ng/mL | Standard Deviation 2.14 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | 11.3 ng/mL | Standard Deviation 1.78 |
Primary
Time to Maximum Observed Concentration (Tmax) of Guaifenesin
Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 8.5, 9, 9.5, 10, 11, 13, 16, 20, 24, and 26 hours Post dose
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Time to Maximum Observed Concentration (Tmax) of Guaifenesin | 1.08 hr | Standard Deviation 0.551 |
| Treatment C (Test) - Plasma Guaifenesin | Time to Maximum Observed Concentration (Tmax) of Guaifenesin | 1.04 hr | Standard Deviation 0.415 |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Time to Maximum Observed Concentration (Tmax) of Guaifenesin | 9.59 hr | Standard Deviation 2.16 |
| Treatment C (Test) - Plasma Hydrocodone Bitartrate | Time to Maximum Observed Concentration (Tmax) of Guaifenesin | 9.33 hr | Standard Deviation 2.09 |
Secondary
Number of Adverse Events(AEs) Experienced by Participants
Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities; subject may have experienced slight discomfort. Moderate = AE resulted in some limitation of usual activities; subject may have experienced significant discomfort. Severe = AE resulted in an inability to carry out usual activities; subject may have experienced intolerable discomfort/ pain. Relationship to Investigational Medicinal Products (IMP) Unlikely = Slight, but remote, chance that AE was caused by IMP. Possible = Reasonable suspicion that the AE was caused by IMP. Probable = Most likely that AE was caused by IMP.
Time frame: Upto Day 17
Population: Pharmacokinetic (PK) Data Sets
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Mild | 7 Events |
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Moderate | 0 Events |
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Severe | 0 Events |
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Unlikely | 4 Events |
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Possible | 3 Events |
| Treatment A (Reference) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Probable | 0 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Probable | 5 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Mild | 12 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Unlikely | 0 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Possible | 8 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Moderate | 1 Events |
| Treatment C (Test) - Plasma Guaifenesin | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Severe | 0 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Moderate | 0 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Severe | 0 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Probable | 16 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Unlikely | 1 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | TEAE by severity: Mild | 25 Events |
| Treatments B (Reference) - Plasma Hydrocodone Bitartrate | Number of Adverse Events(AEs) Experienced by Participants | Relationship to IMP - Possible | 8 Events |