A Comparative Bioavailability/Food Effect Study of Immediate-Release and Extended-Release Tramadol HCl/Acetaminophen Combination Products Following Single-Dose and Multiple-Dose Administration in Healthy Adult Volunteers

The objectives of this two-part study were to compare the single-dose and multiple-dose pharmacokinetics of extended release and immediate-release fixed combination formulations containing tramadol-HCl/acetaminophen and to evaluate the effect of food on the extended-release formulation.

• To compare the single (Part A) and multiple dose (Part B) pharmacokinetic profiles and bioavailability of DDS-06C tablets with the immediate-release tablet reference products Zaldiar® and Ultracet®.
• To assess the effect of food on the pharmacokinetic profile of DDS-06C tablets following administration of a single oral dose.
• To monitor and record all adverse events.

• Drug: DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl)
  DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl: two tablets, single dose, total administered of 1300 mg acetaminophen/150 mg tramadol HCl under fasting conditions
• Drug: DDS-06C (650 mg acetaminophen and 75 mg tramadol)
  DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl: two tablets, single dose, total administered of 1300 mg acetaminophen/150 mg tramadol HCl under fed conditions
• Drug: Zaldiar®
  Zaldiar® (325 mg acetaminophen and 37.5 mg tramadol HCl): two tablets; dose of 650 mg acetaminophen/75 mg tramadol HCl administered at Time = 0 hr (fasting)and second dose at Time = 6 hr (fed) Ultracet® (325 mg acetaminophen and 37.5 mg tramadol HCl)
• Drug: Ultracet®
  Ultracet® (325 mg acetaminophen and 37.5 mg tramadol HCl)two tablets; dose of 650 mg acetaminophen/75 mg tramadol HCl administered at Time = 0 hr (fasting)and second dose at Time = 6 hr (fed) Ultracet® (325 mg acetaminophen and 37.5 mg tramadol HCl)
• Drug: Two tablets of DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl), multiple doses, under both fed and fasting conditions
  Two tablets of DDS-06C, twice daily at 12-hour intervals under fed conditions for the first 4 days, then under fasting conditions for the 5th day. The total daily dose administered was 2600 mg Acetaminophen/300 mg tramadol HCl
• Drug: Zaldiar®, multiple doses,(fed & fasting):
  Two tablets of Zaldiar®, 4 times daily at 6-hour intervals under fed conditions for the first 4 days, then under fasting conditions for the 5th day. The total daily dose administered was 2600 mg Acetaminophen/300 mg tramadol HCl
• Drug: Ultracet®, multiple doses, (fed & fasting)
  Two tablets of Ultracet®, 4 times daily at 6-hour intervals under fed conditions for the first 4 days, then under fasting conditions for the 5th day. The total daily dose administered was 2600 mg Acetaminophen/300 mg tramadol HCl

• Experimental: Part A, Arm A
  Intervention: Drug: DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl)
• Experimental: Part A, Arm B
  Intervention: Drug: DDS-06C (650 mg acetaminophen and 75 mg tramadol)
• Active Comparator: Part A, Arm C
  Intervention: Drug: Zaldiar®
• Active Comparator: Part A, Arm D
  Intervention: Drug: Ultracet®
• Experimental: Part B, Arm E
  Intervention: Drug: Two tablets of DDS-06C (650 mg acetaminophen and 75 mg tramadol HCl), multiple doses, under both fed and fasting conditions
• Active Comparator: Part B, Arm F
  Intervention: Drug: Zaldiar®, multiple doses,(fed & fasting):
• Active Comparator: Part B, Arm G
  Intervention: Drug: Ultracet®, multiple doses, (fed & fasting)

Inclusion Criteria:

• Adult males or females aged 18-55 years inclusive with body mass index (BMI) between 18-30 kg/m2
• Healthy as determined by pre-study medical history, physical examination and 12-lead ECG
• Clinical laboratory tests within the reference ranges or clinically acceptable to the Investigator
• Negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) I and II tests at screening
• Negative for drugs of abuse and alcohol at screening and admission
• Non-smokers for at least 3 months preceding screening
• If female, were not currently pregnant or breast feeding and were using medically acceptable methods of contraception and if male, were themselves and their female partners using medically acceptable methods of contraception
• Able and willing to give written informed consent.

Exclusion Criteria:

• Subjects who did not conform to the above inclusion criteria
• Female subjects who were pregnant, trying to become pregnant, lactating or not using acceptable methods of contraception
• Clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders
• Clinically relevant surgical history
• Clinically relevant family history
• History of relevant atopy
• History of relevant drug hypersensitivity
• History of alcoholism
• History of drug abuse
• Male subjects who consumed more than 21 units of alcohol a week and female subjects who consumed more than 14 units of alcohol a week
• Significant infection or known inflammatory process on screening
• Acute gastrointestinal symptoms at the time of screening and/or admission (e.g. nausea, vomiting, diarrhoea, heartburn)
• Acute infection such as influenza at the time of screening or admission
• Use of prescription drugs within 7 days of first dosing, unless agreed as non clinically relevant by the Principal Investigator and Sponsor
• Use of over-the-counter medication excluding routine vitamins but including mega dose vitamin therapy within 14 days of first dosing, unless agreed as non clinically relevant by the Principal Investigator and Sponsor
• Use of any investigational drug or participation in any clinical trial within 3 months of their first dosing
• Donation or receipt of any blood or blood products within the previous 3 months prior to first dosing
• Vegetarians, vegans or having medical or cultural dietary restrictions.
• Inability to communicate reliably with the Investigator.
• Subjects who were unlikely to co-operate with the requirements of the study