AimsPreclinical studies of MR309, a selective sigma‐1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309.MethodsSteady‐state PK of MR309 (400 mg once daily and 200 mg twice‐daily [BID] for 10 days; EudraCT 2015–001818‐99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017–000670‐11 [positron emission tomography study]) were investigated in healthy volunteers. Positron emission tomography using the σ1R ligand [11C]SA4503 was conducted at baseline, and 2 and 8 hours after a single dose of MR309 (200–800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data‐driven model fitting.ResultsMR309 was well tolerated, brain σ1R occupancy ranged between 30.5 and 74.9% following single‐dose MR309 (n = 7). MR309 BID provided a plasma PK profile with less fluctuation than once daily dosing (n = 16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59–74%.ConclusionMR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications.

Introduction: Pain management is a major unmet need due to the suboptimal efficacy and undesirable side effects of current analgesics. Multimodal therapies recruiting complementary mechanisms of action may help address this. Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy, particularly if modification of the physicochemical properties of constituent APIs can be translated into clinical benefits.Areas covered: The preclinical and clinical profiles of Co-Crystal of Tramadol-Celecoxib (CTC), a novel API-API co-crystal (1:1 molecular ratio of rac-tramadol.hydrochloride and celecoxib) are described.Expert opinion: CTC may provide a relevant addition to pain therapy due to its: i) unique co-crystal structure conferring differentiated intrinsic dissolution profiles on constituent APIs, ii) modified clinical pharmacokinetics (slower absorption of tramadol and faster absorption of celecoxib) compared with commercially available single-entity reference products (in agreement with modified dissolution rates), iii) superior benefit-risk ratio compared with reference products (suggested by preclinical synergistic antinociceptive effects, without potentiation of adverse effects), and iv) efficacy in a phase 2 trial of moderate to severe pain following extraction of 2 impacted third molars requiring bone removal, where CTC doses containing low doses of APIs exerted a significant effect. Phase 3 studies are currently ongoing.

Introduction: Pain management is a major unmet need due to the suboptimal efficacy and undesirable side effects of current analgesics. Multimodal therapies recruiting complementary mechanisms of action may help address this. Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy, particularly if modification of the physicochemical properties of constituent APIs can be translated into clinical benefits.Areas covered: The preclinical and clinical profiles of Co-Crystal of Tramadol-Celecoxib (CTC), a novel API–API co-crystal (1:1 molecular ratio of rac-tramadol.hydrochloride and celecoxib) are described.Expert opinion: CTC may provide a relevant addition to pain therapy due to its: i) unique co-crystal structure conferring differentiated intrinsic dissolution profiles on constituent APIs, ii) modified clinical pharmacokinetics (slower absorption of tramadol and faster absorption of celecoxib) compared with commercially available single-entity reference products (in agreement with modified dissolution rates), iii) superior benefit–risk ratio compared with reference products (suggested by preclinical synergistic antinociceptive effects, without potentiation of adverse effects), and iv) efficacy in a phase 2 trial of moderate to severe pain following extraction of ≥2 impacted third molars requiring bone removal, where CTC doses containing low doses of APIs exerted a significant effect. Phase 3 studies are currently ongoing.

Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API–API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib). Tramadol and celecoxib pharmacokinetics are modified after CTC administration versus administration of reference products. This randomised, open-label, crossover, phase 1 study assessed CTC pharmacokinetics, dose proportionality, safety and tolerability in Japanese and Caucasian subjects.

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.

AbstractBackground and AimsTake‐home naloxone can prevent death from heroin/opioid overdose, but pre‐provision is difficult because naloxone is usually given by injection. Non‐injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.DesignOpen‐label, randomized, five‐way cross‐over PK study.SettingClinical trials facility (Croydon, UK).ParticipantsThirty‐eight healthy volunteers (age 20–54 years; 11 female).Intervention and comparatorThree doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone.MeasurementsRegular blood samples were taken, with high‐frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.FindingsMean peak concentration (Cmax) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (Tmax). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47–51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3‐minute intervals showed that comparable plasma naloxone concentrations would be anticipated.ConclusionsConcentrated 2 mg intranasal naloxone is well‐absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post‐dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.

BACKGROUND AND AIMS Lack of non-injectable naloxone formulations has impeded widespread take-home provision for the prevention of heroin/opioid overdose deaths. For non-injectable formulations that are finally being investigated, rapid onset of action and sufficient bioavailability will be vital. We present analysis of data from a study of concentrated naloxone nasal spray formulations. Our aims are: to assess (1) pharmacokinetic properties and (2) suitability for overdose reversal in terms of naloxone absorption within 30 minutes post-dosing. DESIGN AND INTERVENTIONS/COMPARATOR Open-label, randomized, four-way cross-over Latin-square pharmacokinetic study of naloxone administration by three routes: intranasal at two doses (8 mg/0.4 ml, 16 mg/0.4 ml) versus sublingual (16 mg/ml) versus intravenous reference (1 mg/ml). SETTING Clinical Pharmacology Unit at The Ohio State University (Columbus, OH, USA). PARTICIPANTS Twelve healthy volunteers (age 20-41; seven female). MEASUREMENTS From blood plasma naloxone concentrations, (1) standard pharmacokinetic parameters, including maximum plasma concentration (Cmax ) and mean absolute bioavailability (F%, relative to intravenous injection), were determined; as well as (2) partial area under the curve (AUC) values, tmax (time to maximum plasma concentration) and t50% (time to 50% of maximum plasma concentration) as measures of early absorption. FINDINGS (1) Bioavailability was F% = 25-28% for intranasal naloxone. Sublingual had low bioavailability (F% = 2%) and was not considered further. Mean Cmax values for 8 mg (12.83 ng/ml) and 16 mg (18.25 ng/ml) intranasal exceeded 1 mg intravenous (9.64 ng/ml) naloxone. (2) Following intranasal administration, t50% was reached within 8 minutes and tmax within 20 minutes. Mean naloxone absorption from dosing to 30 minutes (AUC30 ) was greater following 8 mg (4.17 h × ng/ml) and 16 mg (5.91 h × ng/ml) intranasal than following 1 mg intravenous (1.70 h × ng/ml) administration. CONCLUSIONS Concentrated naloxone nasal spray has a promising pharmacokinetic profile, with substantial bioavailability. Its early absorption time-course suggests that concentrated nasal naloxone is suitable for emergency administration in the community, where rapid restoration of respiratory function is essential for opioid overdose reversal.

OBJECTIVE:To determine the absolute bioavailability of naloxone from oral doses ranging from 5 mg to 120 mg.MATERIALS AND METHODS:In this open-label study, 28 healthy subjects received naloxone 1 mg (0.4 mg/ml) as an intravenous infusion (reference treatment), and the following oral doses as prolonged release (PR) naloxone tablets: 5 mg, 20 mg, 40 mg, 80 mg and 120 mg. The pharmacokinetic characteristics of 40 mg administered per rectum were also investigated. Each subject received five of the seven treatments as single doses with a 7 day washout between doses. Pharmacokinetic blood sampling and safety monitoring were performed for 24 h after the intravenous dose, and 72 h after the oral and rectal doses.RESULTS:The mean absolute bioavailability of naloxone from the orally administered PR tablets was very low, ranging from 0.9% for the 5 mg dose to 2% for the 40, 80 and 120 mg doses, based on AUC(t) values. The pharmacokinetics of naloxone were linear across the range of oral doses. Where AUC(inf) values were calculated, these confirmed the results based on AUC(t) values (mean absolute bioavailability ranging from 1.9% to 2.2% for the 20 mg to 120 mg oral doses). The absolute bioavailability of naloxone was higher following rectal administration compared with oral administration, but was still low at 15%.CONCLUSIONS:The mean oral absolute bioavailability of naloxone in this study was ≤ 2% at doses ranging from 5 mg to 120 mg.

Objectives: This exploratory study in healthy volunteers investigated the effect of single doses of oxycodone on gastrointestinal (GI) transit time and the degree to which a single dose of naloxone reverses the oxycodone-induced effect. Methods: Fifteen healthy male volunteers received: oxycodone 10 and 20 mg, oxycodone/naloxone 10/5 and 20/10 mg (all as prolonged release tablets) and placebo. Each dose was radiolabelled and administered with a capsule containing radiolabelled resin (surrogate for GI contents). Results: Scintigraphic analysis showed that 20 mg oxycodone significantly increased colon arrival time (mean 7.19 vs 5.15 h for placebo, p = 0.0159). Mean colon arrival time for oxycodone/naloxone 20/10 mg (5.16 h) was similar to placebo, although the difference between oxycodone/naloxone 20/10 mg versus oxycodone 20 mg was not significant (p = 0.0653). Colonic geometric centre analysis showed a significant increase in mean time for the resin to reach the colon following oxycodone 10 and 20 mg compared with placebo (increases of 5.3 and 8.8 h). There was no significant effect of naloxone at the lower dose; however, oxycodone/naloxone 20/10 mg significantly reduced mean colonic transit time by 2.1 h (p = 0.0376). Conclusion: A single dose of oxycodone 20 mg significantly prolonged GI transit time but this effect was reduced by co-administration of naloxone.

Background: There is an increasing body of evidence supporting the need for prophylactic management of the adverse events (AEs) associated with long-term opioid use in patients with chronic pain. Symptoms of bowel dysfunction, such as constipation, may have a significant impact on a patient's quality of life and willingness to continue opioid therapy, and therefore should be managed proactively to ensure that the patient can continue effective pain management. The fixed-dose combination (FDC) prolonged-release (PR) oxycodone/naloxone (OXN) may be an effective therapeutic approach to delivering analgesia, with a reduced risk for opioid-induced constipation.Objective: The aim of this paper was to report the pharmacokinetic results from a single-dose study and a multiple-dose bioequivalence study of OXN versus separate formulations of oxycodone PR and naloxone PR administered concurrently in healthy subjects.Methods: Both studies were open-label, randomized crossover studies in healthy adult male and female subjects. In the single-dose study, subjects were randomly assigned to 1 of 4 treatment groups: OXN FDC (4 x 10/5-mg, 2 x 20/10-mg, or 1 x 40/20-mg dose strength [each given at a total combined dose of 40/20 mg]) or oxycodone PR 40 mg + naloxone PR 20 mg given in separate formulations. In the multiple-dose study, 34 subjects were randomly assigned to 1 of 3 treatment groups: OXN FDC 40/20 mg, oxycodone PR 40 mg, or naloxone PR 20 mg. Treatments were considered bioequivalent if the 90% CIs for relative bioavailability calculations fell within a predetermined range of 80% to 125%. AEs were assessed by the investigator at each study visit.Results: The single-dose study included 28 subjects (22 men, 6 women; mean [SD] age, 32.3 [5.4] years; weight, 75.5 [9.3] kg; and body mass index [BMI], 24.2 [2.5] kg/m(2)). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 473.49 (72.16), 491.22 (82.18), 488.89 (91.04), and 502.28 (84.1.3) ng . h/mL, respectively; mean C-max values were 34.91 (4.36), 35.73 (4.93), 34.46 (5.03), and 40.45 (4.71) ng/mL. For naloxone-3-glucuronide (the primary analyte of naloxone), the mean (SD) AUC(t) values with OXN 1015, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 539.93 (142.24), 522.45 (128.57), 520.10 (133.18), and 523.37 (11.9.75) ng . h/mL, respectively; mean C-max values were 62.01 (15.96), 63.62 (19.51), 61.95 (18.37), and 63.55 (16.75) ng/mL. There were no statistically significant differences between the treatments, and each of the treatment comparisons resulted in 90% CIs within the range for bioequivalence. The multiple-dose steady-state bioequivalence study included 34 subjects (28 men, 6 women; mean [SD] age, 36 [9.4] years; weight, 78.9 [11.7] kg; and BMI, 24.6 [1.9] kg/m(2)). No significant differences were observed between the treatments, with the exception of naloxone-3-glucuronide C-min,C-ss values. Mean C-min,C-ss values of 22.6 and 24.0 ng/mL were obtained for the OXN combination and naloxone PR tablet, respectively. In the multiple-dose study, the most frequently reported AEs with OXN, oxycodone PR, and naloxone PR were headache (7%, 26%, and 17%, respectively), anorexia (10%, 16%, and 13%), and nausea (10%, 13%, and 7%).Conclusions: The results from the single-dose study were Consistent with the regulatory definition of bio-equivalence of the FDCs and single components across the range of doses administered. The pharmacokinetic properties of the OXN FDC were similar to those of oxycodone PR + naloxone PR given as separate formulations, based on the regulatory definition. These findings were consistent with the results of the multiple-dose steady-state bioequivalence study. In this population of healthy Volunteers, the pharmacokinetic properties of oxycodone apparently were not significantly influenced by administering oxycodone in a combination product, and the availability of naloxone-3-glucuronide from OXN was similar to that from the naloxone PR tablet. These findings suggest that the coadministration of oxycodone PR and naloxone PR in an FDC would not significantly affect the bioavailability of either of its constituents in these subjects. (Clin Ther. 2008;30:2051-2068) (C) 2008 Excerpta Medica Inc.

Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients' quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a mu-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.