A Four-Period, Four-Treatment, Four-Way Relative Bioavailability Study of CL-108 Under Fed and Fasted Conditions

• CL-108 (Drug): Hydrocodone bitartrate/acetaminophen/promethazine 7.5 mg/325 mg/12.5 mg single dose by mouth
• Vicoprofen (Drug): Hydrocodone Bitartrate and Ibuprofen 7.5 mg/200 mg single dose tablet by mouth
• Ultracet (Drug): Tramadol HCl/acetaminophen 37.5 mg/325 mg single dose tablet by mouth
• Phenergan (Drug), also known as Promethazine HCl: Phenergan (Promethazine HCl, USP) 12.5 mg single dose tablet by mouth

Primary outcomes

• Maximum Drug Concentration (Cmax) in Plasma Determined Directly From Individual Concentration-time Data [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Cmax of CL-108 and Vicoprofen + Ultracet + Phenergan were measured in the plasma (the liquid component of the blood in which the blood cells are suspended) in samples collected up to 48 hours post-dose.
• Time to Reach Maximum Concentration (Tmax) [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]
• Last Quantifiable Drug Concentration (Clast) Determined Directly From Individual Concentration-time Data [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]
• Time of the Last Quantifiable Concentration (Tlast) [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]
• Observed Elimination Rate Constant (λz) [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile
• Observed Terminal Elimination Half-life (T1/2) [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Calculated as: T1/2 = ln(2)/λz
• Area Under the Plasma Concentration-time Curve (AUC0-0.25) for Hydrocodone and Promethazine [0 (pre-dose) to 0.25 hours post-dose]: AUC0-0.25 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-0.50 for Hydrocodone and Promethazine [0 (pre-dose) to 0.5 hours post-dose]: AUC0-0.50 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-0.75 for Hydrocodone and Promethazine [0 (Pre-dose) to 0.75 hours post-dose]: AUC0-0.75 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-1.0 for Hydrocodone and Promethazine [0 (pre-dose) to 1.0 hours post-dose]: AUC0-1.0 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-1.5 for Hydrocodone and Promethazine [0 (pre-dose) to 1.5 hours post-dose]: AUC0-1.5 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-2.0 for Hydrocodone and Promethazine [0 (pre-dose) to 2 hours post-dose]: AUC0-2.0 measured by Linear Trapezoidal with Linear Interpolation method.
• AUC0-4.0 for Hydrocodone and Promethazine [0 (pre-dose) to 4 hours post-dose]: AUC0-4.0 measured by Linear Trapezoidal with Linear Interpolation method.
• Area Under the Plasma Concentration-time (AUClast) Curve From Time-zero to the Time of the Last Quantifiable Concentration [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Calculated using the linear trapezoidal rule
• Area Under the Concentration-time (AUCinf) Curve From Time-zero Extrapolated to Infinity [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Calculated as: AUCinf = AUClast + Clast/λz
• Percentage of AUCinf [AUCExtrap (%)] Based on Extrapolation [0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours post-dose]: Calculated as: AUCExtrap (%) = (AUC0-inf - AUC0-last)/AUC0-inf *100

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Inclusion Criteria:

* Written informed consent
* Subject's body mass index (BMI) must be between 18 and 30kg/m2 (inclusive), and subject must weigh a minimum of 50 kg (110lb)
* Abide by study restrictions
* Acceptable birth control measures
* Ability to attend all study visits
* Vital signs as per protocol
* Willing to consume high calorie meals within designated time frame

Exclusion Criteria:

* Clinically significant medical history
* Clinically significant abnormal findings
* History or presence of allergic or adverse response to hydrocodone, ibuprofen,acetaminophen, any non-steroidal anti-inflammatory drugs (NSAIDs), promethazine, or related drugs.
* Has smoked or used tobacco products within 60 days prior to the first dose of study medication
* Has donated blood or plasma within 30 days prior to the first dose of study medication
* Has participated in another clinical trial (randomized subjects only) within 30 days prior to the first dose of study medication.

Participant flow

Outcome results

• Maximum Drug Concentration (Cmax) in Plasma Determined Directly From Individual Concentration-time Data (Primary), Mean, ng/mL: Treatment A: CL-108 (Fasted) 20.0 +/- 5.48; Treatment B: CL-108 (Fed) 17.9 +/- 5.80; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 18.4 +/- 5.62; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 17.5 +/- 3.63
• Time to Reach Maximum Concentration (Tmax) (Primary), Mean, hours: Treatment A: CL-108 (Fasted) 1.55 +/- 0.71; Treatment B: CL-108 (Fed) 3.38 +/- 1.58; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 1.39 +/- 1.22; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 3.09 +/- 1.89
• Last Quantifiable Drug Concentration (Clast) Determined Directly From Individual Concentration-time Data (Primary), Mean, ng/mL: Treatment A: CL-108 (Fasted) 0.556 +/- 0.354; Treatment B: CL-108 (Fed) 0.523 +/- 0.412; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 0.465 +/- 0.315; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 0.527 +/- 0.424
• Time of the Last Quantifiable Concentration (Tlast) (Primary), Mean, Hours: Treatment A: CL-108 (Fasted) 27.80 +/- 8.99; Treatment B: CL-108 (Fed) 31.21 +/- 11.28; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 28.81 +/- 9.84; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 31.58 +/- 11.46
• Observed Elimination Rate Constant (λz) (Primary), Mean, h-1: Treatment A: CL-108 (Fasted) 0.1468 +/- 0.0293; Treatment B: CL-108 (Fed) 0.1373 +/- 0.0258; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 0.1415 +/- 0.0292; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 0.1371 +/- 0.0271
• Observed Terminal Elimination Half-life (T1/2) (Primary), Mean, hours: Treatment A: CL-108 (Fasted) 4.93 +/- 1.11; Treatment B: CL-108 (Fed) 5.22 +/- 0.99; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 5.13 +/- 1.18; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 5.26 +/- 1.08
• Area Under the Plasma Concentration-time Curve (AUC0-0.25) for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 0.08870 +/- 0.1318; Treatment B: CL-108 (Fed) 0.03786 +/- 0.1269; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 0.1219 +/- 0.2151; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 0.02250 +/- 0.04577
• AUC0-0.50 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 0.9532 +/- 0.9498; Treatment B: CL-108 (Fed) 0.2566 +/- 0.6382; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 1.280 +/- 1.271; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 0.3163 +/- 0.4305
• AUC0-0.75 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 3.194 +/- 2.379; Treatment B: CL-108 (Fed) 0.8759 +/- 1.645; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 4.027 +/- 3.092; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 1.276 +/- 1.629
• AUC0-1.0 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 6.383 +/- 3.637; Treatment B: CL-108 (Fed) 2.046 +/- 3.244; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 7.524 +/- 4.678; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 2.722 +/- 3.329
• AUC0-1.5 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 14.33 +/- 4.971; Treatment B: CL-108 (Fed) 5.782 +/- 7.049; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 14.95 +/- 6.822; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 6.424 +/- 6.742
• AUC0-2.0 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 23.21 +/- 6.240; Treatment B: CL-108 (Fed) 10.95 +/- 10.34; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 22.53 +/- 8.183; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 11.04 +/- 10.12
• AUC0-4.0 for Hydrocodone and Promethazine (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 54.04 +/- 13.77; Treatment B: CL-108 (Fed) 38.97 +/- 18.47; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 48.35 +/- 12.87; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 35.14 +/- 17.97
• Area Under the Plasma Concentration-time (AUClast) Curve From Time-zero to the Time of the Last Quantifiable Concentration (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 146.2 +/- 56.77; Treatment B: CL-108 (Fed) 151.9 +/- 58.79; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 130.9 +/- 47.94; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 148.5 +/- 56.84
• Area Under the Concentration-time (AUCinf) Curve From Time-zero Extrapolated to Infinity (Primary), Mean, h*ng/mL: Treatment A: CL-108 (Fasted) 150.2 +/- 57.30; Treatment B: CL-108 (Fed) 155.8 +/- 58.75; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 134.3 +/- 48.20; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 152.4 +/- 56.83
• Percentage of AUCinf [AUCExtrap (%)] Based on Extrapolation (Primary), Mean, Percentage of AUCExtrap: Treatment A: CL-108 (Fasted) 2.72 +/- 1.72; Treatment B: CL-108 (Fed) 2.68 +/- 1.97; Treatment C: Vicoprofen, Ultracet and Phenergan (Fasted) 2.65 +/- 1.78; Treatment D: Vicoprofen, Ultracet and Phenergan (Fed) 2.71 +/- 2.06

Adverse events

Time frame: Up to day 72

Other adverse events by term