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

Abstract

Background and ObjectiveCo-Crystal of Tramadol–Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions.MethodsHealthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed.ResultsThirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O-desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration–time curve to infinity (AUC∞) were within the pre-defined range for comparative bioavailability (80–125%). For celecoxib, Cmax and AUC∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98–146.49) and 129.34% (121.78–137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions.ConclusionsAs reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability.Clinical trial registration number152052 (registered with the Therapeutic Products Directorate of Health Canada)Electronic supplementary materialThe online version of this article (10.1007/s40261-018-0672-y) contains supplementary material, which is available to authorized users.

Celecoxib‐tramadol co‐crystal in patients with moderate‐to‐severe pain following bunionectomy with osteotomy: A phase 3, randomized, double‐blind, factorial, active‐ and placebo‐controlled trial

“…The molecular structure of CTC shows that its three constituent moieties (celecoxib and the two active enantiomers of tramadol) are linked via hydrogen bonding in which chloride ions establish three key intermolecular contacts with adjacent molecules 2–4 . This molecular structure of CTC changes the physicochemical properties of celecoxib and tramadol in a way not achieved by their fixed‐dose or free combination, 4,5 modifying the pharmacokinetics of each as demonstrated in several clinical crossover studies 6–9 . In particular, tramadol from CTC has a lower maximum plasma concentration compared with tramadol taken alone or concomitantly with celecoxib, celecoxib absorption is accelerated with CTC compared with celecoxib alone, and tramadol‐mediated interference of celecoxib absorption is minimized with CTC compared with concomitant administration of celecoxib and tramadol 6–8 .…”

Differential Solution Behavior of the New API–API Co-Crystal of Tramadol–Celecoxib (CTC) versus Its Constituents and Their Combination

“…The FeSSIF-V2 dissolution curve shows an initial supersaturation state that reverts after 2 h, but maintains a clear superior release in relation to the other formulations (about 7-fold higher versus FaSSIF-V2). This study was shown to be highly predictive of the results obtained in the food interaction clinical study, where increased bioavailability and delayed absorption of CXB were identified as food effects. In fact, CXB administration was already known to be affected by the presence of food both in vitro (7-fold times higher) and in the clinic .…”

A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children

“…The bioavailability of the chocolate-based drug delivery system tablet relative to the liquid tramadol formulation was estimated to be 125%. Tramadol is completely absorbed (90-100%) upon oral administration [26] and the presence of fats in the chocolate base could not have further enhanced tramadol bioavailability [28]. Thus, it may well be that the liquid tramadol formulation was 20% less bioavailable compared with the chocolate-based drug delivery system tablet.…”