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

Abstract

AimWe 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.MethodsHealthy 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.ResultsA 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 (C max)]; 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 C max 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.ConclusionAfter 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.

The Effect of Food on Tramadol and Celecoxib Bioavailability Following Oral Administration of Co-Crystal of Tramadol–Celecoxib (CTC): A Randomised, Open-Label, Single-Dose, Crossover Study in Healthy Volunteers

“…The total number of AEs and the number of subjects who experienced at least one AE were similar under both conditions. The most frequently observed AEs were consistent with commonly reported AEs from previous Phase 1 and Phase 2 studies of CTC [ 10 – 12 ] and for standard drug formulations of tramadol and celecoxib [ 13 , 14 ].…”

“…The data reported herein are supported by findings from other CTC clinical trials. The fasting pharmacokinetic data obtained in the present study are similar to those collected in earlier Phase 1 studies of CTC, in which dosing was carried out under fasting conditions [ 11 , 12 ]. In the present study, median T max values of celecoxib and tramadol after CTC dosing under fasting conditions were 1.25 and 2.67 h, respectively.…”

“…Each subject received a single oral dose of 200 mg CTC, once under fed conditions and once under fasting conditions. This dose had previously been evaluated in two earlier Phase 1 studies [ 11 , 12 ] and was also efficacious and well tolerated in a Phase 2 study in which doses of 50, 100, 150 and 200 mg CTC were administered [ 10 ]. CTC (Esteve Pharmaceuticals, S.A., Spain) was provided as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib.…”

“…The clinical pharmacokinetics of CTC were first characterised in two Phase 1 studies conducted in healthy male and female subjects; one assessing a single dose of CTC [ 11 ] and one assessing multiple doses [ 12 ]. In both studies, differences in the pharmacokinetics of tramadol and celecoxib were seen after administration of CTC compared with after administration of the individual reference products (immediate-release tramadol or celecoxib) alone or in free combination.…”

“…In the case of tramadol, a lower maximum observed plasma concentration ( C max ), slightly prolonged time to C max ( T max ) and similar area under the plasma concentration–time curve (AUC) were observed with CTC. In the case of celecoxib pharmacokinetics after CTC administration, celecoxib had a lower C max compared with celecoxib alone, and a faster T max compared with celecoxib alone or in free combination with tramadol [ 11 , 12 ].…”