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Purpose Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. Methods This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0–T, and AUC0–∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0–T, and AUC0–∞ was based on ln-transformed data, and Tmax was rank-transformed. Findings Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0–T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. Implications The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. (Clin Ther. 2021;43:XXX–XXX) © 2021 Elsevier HS Journals, Inc.

SummaryAim We compared the pharmacokinetic (PK) profiles of Co-Crystal of Tramadol-Celecoxib (CTC) versus 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 wash-out): 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). 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 Thirty 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 of each active pharmaceutical ingredient in CTC were modified by co-crystallization compared with reference products alone or in open combination.

Aim Co-Crystal of Tramadol-Celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients (APIs) under development by Esteve (E-58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products (immediate-release [IR] tramadol and celecoxib) alone and in open combination. Methods Healthy adults aged 18–55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg 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). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). Results Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml-1 (mean maximum plasma concentration [Cmax]); 3039, 2979 and 3119 ng h ml-1 (mean cumulative area under the plasma concentration–time curve [AUCτ]); and 2.7, 1.8 and 1.8 h (median time to Cmax [Tmax]). For Treatments-1, -3 and -4, celecoxib PK parameters were 313, 449 and 284 ng ml-1; 2183, 3093 and 2856 ng h ml-1; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. Conclusion PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.

Background and Objective Co-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. Methods Healthy 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. Results Thirty-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. Conclusions As 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 number 152052 (registered with the Therapeutic Products Directorate of Health Canada) Electronic supplementary material The online version of this article (10.1007/s40261-018-0672-y) contains supplementary material, which is available to authorized users.

Background Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available. Objective The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions. Study Design This was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study. Setting The study was conducted in a phase I clinical unit. Subjects and Methods A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. Results In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [Cmax] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUCt] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean Cmax 120.99 ng/mL, CV 15.0%; mean AUCt 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed: fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for Cmax and AUCt were within the range of 80–125%. Conclusion High-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.

Background Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. Objective The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. Study Design This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. Setting The study was conducted in a phase I clinical unit. Subjects and Methods A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). Results In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration–time curve from time zero to time t (AUCt) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUCt 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7 %; mean AUCt 1630.85 ng·h/mL, CV 22.8 %]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence. Conclusions Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.