E. Ismatova, K. Jang, J. Lee, H. Lee, S. Shin, K. Yu, I. Jang; Seoul National University Hospital, Clinical Pharmacology and Therapeutics, Seoul, Korea, Republic of

BACKGROUND: ULTRACET® ER is a combination of tramadol and acetaminophen (APAP) used to treat moderate to severe pain. This study aimed to demonstrate the bioequivalence between the current formulations “Marketed ULTRACET® ER” (Tramadol HCl / Acetaminophen 75 mg/650 mg) and a new formulation using an optimized manufacturing process “New ULTRACET® ER."
METHODS: A randomized, open-label, two-period crossover study in 56 healthy male subjects under fasting condition was conducted. The subjects were divided into two treatment sequence groups AB and BA (A: New ULTRACET® ER; B: Marketed ULTRACET® ER) with single dose administration and a wash-out period of 7 days. Blood samples were collected during the 48-hour period after the drug administration. The following plasma pharmacokinetic parameters were calculated: Cmax, AUClast, AUCinf. The point estimate and 90% confidence intervals for the ratio of geometric means for Cmax and AUCinf between two treatment groups were determined as a criterium for bioequivalence assessment.
RESULTS: The point estimates (90% CIs) of the geometric mean ratio (GMR) of the Cmax, AUClast and AUCinf for APAP were 104.5% (99.5-109.8), 100.6% (98.8-102.5) and 100.6% (98.7-102.4); while those for tramadol were 103.8% (100.8-106.8), 101.6% (98.8-104.4) and 101.6% (98.8-104.4), respectively. A total of 26 adverse events (AEs) were reported in 11 out of the 56 subjects. No serious AEs were observed in either treatment group with similar occurrences.
CONCLUSION: The two formulations of ULTRACET® ER were considered to be bioequivalent, since the 90% confidence intervals for GMR between New ULTRACET® ER and Marketed ULTRACET® ER of tramadol and APAP fall within 80 to 125%. Both tablets were well tolerated in healthy male subjects.