These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• A novel and highly selective sigma-1 receptor antagonist (S1RA) provides a new approach for pain management. S1RA has shown activity in animal models of neuropathic pain and potentiation of opioid analgesia. WHAT THIS STUDY ADDS• Phase I studies of single and multiple oral dose administration show that S1RA is safe and well tolerated by healthy subjects. S1RA is rapidly absorbed and its rate and extent of exposure increases with dose.• The safety, tolerability, pharmacokinetic and pharmacodynamic profiles of S1RA support its further phase II development in different pain indications. AIMTo assess the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy subjects of a novel, highly selective, sigma-1 receptor antagonist (S1RA). METHODSThree randomized, double-blind, placebo-controlled trials evaluated single oral doses (5-500 mg, study 101; 500-800 mg, study 106) and multiple doses (50-400 mg once daily for 8 days, study 102) of S1RA. Safety and tolerability were assessed by adverse event reporting, clinical laboratory, physical examinations, vital signs and electrocardiography, including Holter monitoring. Pharmacodynamic assessments included computerized cognitive testing. Plasma samples were analyzed using validated HPLC-MS/MS methods. RESULTSOne hundred and seventy-five subjects were enrolled. Single and multiple doses were safe and well tolerated, with no serious adverse events. The most common side effects were headache and dizziness. The highest single doses were associated with some mild to moderate transient CNS effects. The maximum tolerated dose was not reached. There were no clinically significant changes in the electrocardiogram (ECG), 24 h Holter monitoring, or in vital signs and laboratory assessments. Subjective CNS pharmacodynamics evaluations showed no relevant differences vs. placebo. Cognitive testing showed no effects on visual memory, executive function, attention or somnolence, while revealing some transient slowing of response for simple reaction time and choice reaction time at 2 h following the administration of higher doses. A fast absorption, rapid distribution and slow elimination were observed (tmax 0.75-2.0 h, t1/2 compatible with once a day administration) and steady-state was reached. No gender differences were observed. CONCLUSIONSS1RA exhibited an acceptable safety, tolerability, pharmacodynamic and pharmacokinetic profile in healthy subjects over the dose range studied.
AimsCo‐crystal of tramadol–celecoxib (CTC) is a novel co‐crystal molecule containing two active pharmaceutical ingredients 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.MethodsHealthy 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).ResultsThirty‐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); 3039, 2979 and 3119 ng h ml–1 (mean cumulative area under the plasma concentration–time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective 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.ConclusionPK parameters of each API in CTC were modified by co‐crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.
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.
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 200mg 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 C max , AUC 0-T , and AUC 0-∞ , which were also calculated normalized to the dose. T max was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the twosided 90% CI of the ratio of geometric mean values for the C max , AUC 0-T , and AUC 0-∞ was based on lntransformed data, and T max 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 C max , reduced AUCs, and a faster T max . The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC.
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