This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.Electronic supplementary materialThe online version of this article (10.1007/s13311-017-0572-5) contains supplementary material, which is available to authorized users.

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.

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ABLC, administered every 21 days for 12 months, is useful as secondary prophylaxis in preventing VL relapse in HIV-infected patients, and is well tolerated.

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.