Study to Evaluate Drug-drug Interactions of Guaifenesin and Hydrocodone Bitartrate

Study Overview
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Brief Summary
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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.

Official Title
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A Study Designed to Examine the Potential for a Drug-drug Interaction Between Guaifenesin and Hydrocodone Bitartrate in Normal Healthy Volunteers

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Humibid®
* Drug: Hydrocodone Bitartrate
* Drug: Humibid® and Hydrocodone Bitartrate tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and/or females between the ages of 19 and 55 years, inclusive. 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. Good general health was determined by medical history, physical examination, electrocardiogram (ECG), and clinical laboratory measures. Within 15% of Ideal Body Weight as defined by the 1983 Metropolitan Life chart. Non-tobacco users, who had not used nicotine or nicotine-containing products for at least 1 year. Able to read, understand, and sign the informed consent after the nature of the study had been explained. Negative finding on tests for Hepatitis B and C antigen as well as HIV and pregnancy test (if female). Negative urine screen for drugs of abuse and alcohol at screening and the first check in. Non-alcohol or drug abuser - for alcohol, defined as history of less then 4 drinks daily. Exclusion Criteria: 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. Females who were pregnant or nursing. History of hypersensitivity reaction to the study drugs or related compounds, such as other opioids. Receipt of an investigational drug within 1 month prior to study enrollment. Donation of blood or significant loss of blood within 56 days or plasma within 14 days prior study enrollment. Known or suspected use of illicit drugs (including codeine or hydrocodone, etc.). 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. Consumption of alcohol within 48 hours prior to each dosing period. Consumption of grapefruit 14 days prior to dosing and throughout the study. 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.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Guaifenesin (Humibid®) single extended release 1200 mg tablet administered with 240 mL of room temperature water under fasted conditions. | Drug: Humibid®<br>* Humibid® 1200 mg (single extended release) tablet<br>* Other names: Guaifenesin;|
| Experimental: Treatment B<br>Hydrocodone Bitartrate of 10 mg in 3 oral doses of a single 3.33 mg tablet in three intervals administered with 240 mL of room temperature water in the fasted state. | Drug: Hydrocodone Bitartrate<br>* Hydrocodone Bitartrate (3.33 mg q4h X 3)<br>|
| Experimental: Treatment C<br>Hydrocodone Bitartrate 10 mg in 3 oral doses of a single 3.33 mg tablet in three intervals and guaifenesin (Humibid®) 1200 mg ER administered with 240 mL of room temperature water in the fasted state. | Drug: Humibid® and Hydrocodone Bitartrate tablet<br>* Humibid® 1200 mg (single extended release) tablet and Hydrocodone bitartrate (3.33 mg q4h X 3)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Guaifenesin | Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration) | 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 | 
| 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. | 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 | 
| 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. | 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 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. | 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 | 
| Time to Maximum Observed Concentration (Tmax) of Guaifenesin | Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration. | 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 Terminal Elimination Half-life (T1/2) of Guaifenesin | Apparent first-order terminal elimination half-life was calculated as 0.693/Kel. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Upto Day 17 |