Pharmacokinetics of multiple doses of co-crystal of tramadol–celecoxib: findings from a four-way randomized open-label phase I clinical trial

Abstract

Aim: We compared the pharmacokinetic (PK) profiles of co-crystal of tramadol–celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. Methods: Healthy adults aged 18–50 years received, under fasted conditions, 15 twice-daily doses of the following treatments (separated by ≥14-day washout): 200 mg immediate-release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer-generated randomization. PK parameters were calculated using non-compartmental analysis. Parameters for CTC were adjusted according to reference product dose. Results: A total of 30 subjects (20 males, mean age 35 years) were included. Multiple-dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml−1 [mean maximum plasma concentration (Cmax)]; 4796, 4990 and 5284 ng h ml−1 (area under the plasma concentration–time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to Cmax at steady state). For treatments 1, 3 and 4, multiple-dose celecoxib PK parameters were 445, 536 and 396 ng ml−1; 2803, 3366 and 2897 ng h ml−1; and 2.0, 2.0 and 3.0 h. Single-dose findings were consistent with multiple-dose data. Types of adverse events were consistent with known reference product safety profiles. Conclusion: After single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co-crystallization compared with reference products alone or in open combination.