Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function.

Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73 m2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study. The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased. The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m2 .

Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI-589 in Healthy Participants.

EPI-589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone-oxidoreductases. Given the effects of EPI-589 on oxidative stress and mitochondrial dysfunction, EPI-589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI-589. Sixty-eight healthy participants were randomly assigned to EPI-589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single-dose administration under fasting conditions, time to maximum plasma concentration (tmax ) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were approximately linear with increases in single doses over a dose range of 250-1000 mg. Under fed conditions, the Cmax decreased to 62.6% of the Cmax under fasting conditions, the AUC was slightly increased, and the tmax was delayed by 1 hour. When EPI-589 was administered daily on days 1 and 7 with twice-daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), Cmax, tmax , and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI-589 was well tolerated as a single daily dose up to 1000 mg and as twice-daily doses up to 750 mg, with a linear pharmacokinetic profile.

Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers.

This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non-Asian participants and investigated the potential for QT/QTc interval prolongation. This five-part (A-E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A-D were randomized, double-blind, placebo-controlled, and included healthy Asian male and female and non-Asian male participants. PK parameters were measured following single-dose napabucasin (80-1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12-lead electrocardiogram (Parts B and C). Part E was open-label, and examined the PK of single-dose napabucasin (240-720 mg) in healthy non-Asian males. Safety and tolerability were measured in Parts A-E. Changes from baseline in the Fridericia-corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed-effects model. Napabucasin was well-tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment-emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single-dose napabucasin (240-1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single-dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.

Pharmacokinetic Evaluation of Blonanserin Transdermal Patch: Population Analysis and Simulation of Plasma Concentration and Dopamine D2 Receptor Occupancy in Clinical Settings.

Blonanserin is an atypical antipsychotic drug with high affinity and selective antagonism for dopamine D2 and D3 and serotonin 5-HT2A receptors. Blonanserin transdermal patch is the first transdermal formulation developed for the treatment of schizophrenia. The purpose of this population pharmacokinetic (PPK) analysis was to evaluate the characteristics of blonanserin pharmacokinetics after transdermal patch application, to estimate the daily fluctuation in blonanserin plasma concentration, and to evaluate the impact of patch application noncompliance to support usage in clinical settings. A total of 3747 plasma blonanserin concentrations from 9 clinical studies (93 healthy volunteers and 348 patients with schizophrenia) were used in the PPK analysis. The plasma concentration was predicted using the final PPK model, and dopamine D2 receptor occupancy was estimated on the basis of the results of a separately reported positron emission tomography study. A 2-compartment, parallel zero-order absorption with a lag time and first-order elimination model was developed to describe the pharmacokinetics of blonanserin, including the change in absorption rate during patch application. The maximum/minimum ratio of plasma concentration was estimated as 1.10 at steady state, indicating minimal fluctuation. In the case of failure to remove the previous patch or a missing application, the increase or decrease in plasma concentration and dopamine D2 receptor occupancy was <20%. These results indicated that the plasma blonanserin concentration and dopamine D2 receptor occupancy were stable after blonanserin transdermal patch application, which may lead to improved tolerability during the treatment of patients with schizophrenia.

Striatal Dopamine D2 Receptor Occupancy Induced by Daily Application of Blonanserin Transdermal Patches: Phase II Study in Japanese Patients With Schizophrenia.

BACKGROUND: Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. METHODS: This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness. RESULTS: Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. CONCLUSIONS: Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia. TRIAL REGISTRY: JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

Pharmacokinetics, safety and metabolite profiling of minesapride, a novel 5-HT4 receptor partial agonist, in healthy elderly and young subjects.

Minesapride is a novel 5-hydroxytryptamine 4 (5-HT4) receptor partial agonist that is expected to show efficacy in patients with irritable bowel syndrome with predominant constipation and functional constipation. An open-label study was conducted to evaluate pharmacokinetics (PK) and safety of minesapride. Japanese subjects, 12 elderly and 12 young, received a single oral dose of minesapride 40 mg/day in the fasted state. Metabolite profiles were also investigated in this clinical study and in an in vitro study using cryopreserved hepatocytes. Clinical results showed that minesapride was rapidly absorbed (Cmax: 2302.1 ng/mL in the elderly group, 2117.5 ng/mL in the young group), and the plasma concentration then decreased with half-life of approximately 7 h. There were no notable PK differences between elderly and young groups. No serious adverse events (AEs) were observed. The only AE that occurred in 2 or more subjects was diarrhea. Metabolite profiles in plasma and urine were similar between elderly and young groups. No major metabolites exceeded 10% of unchanged minesapride, and results of the in vitro study suggested that there were no human-specific metabolites. From the viewpoints of PK and metabolite profiling, no dose adjustment of minesapride is warranted in elderly population without renal or hepatic impairment.

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment.

Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

Thorough QT/QTc Study Shows That a Novel 5-HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation.

Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT4 ) receptor that acts as a partial agonist. Although 5-HT4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

A 3-Part Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DSP-6952 in Healthy Japanese Subjects and Those With ≤3 Spontaneous Bowel Movements per Week.

We hypothesized that DSP-6952, a partial agonist of the 5-hydroxytryptamine type-4 receptor and a gastrointestinal prokinetic agent, can induce natural bowel movements by enhancing gastrointestinal motility and colonic transit in patients with chronic constipation and irritable bowel syndrome with constipation. This 3-part phase 1 study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of DSP-6952. Eighty-eight Japanese subjects (64 healthy volunteers and 24 subjects with spontaneous bowel movements ≤3 times/wk) were randomized to DSP-6952 or placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was similar for DSP-6952 and placebo. The most frequent TEAEs were gastrointestinal disorders; diarrhea was more common with DSP-6952, but only when it was administered to healthy volunteers. Peak plasma concentration (Cmax ) and area under the concentration-time curve (AUC) of DSP-6952 were dose-proportional within a range of 4-120 mg. Under fed conditions, the Cmax and AUC of DSP-6952 were approximately half those of fasting conditions. No abnormal drug accumulation was observed with repeated administration. In subjects with spontaneous bowel movements ≤3 times/wk, the median change in the frequency of bowel movements from baseline increased, although the difference did not reach statistical significance. DSP-6952 was well tolerated at single and multiple doses up to 120 mg/d, with a linear pharmacokinetic profile among all subjects.

Design, synthesis and structure-activity relationships of novel benzoxazolone derivatives as 18 kDa translocator protein (TSPO) ligands.

Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity relationship (SAR) of a series of compounds with various substituents at the amide part and C-5 position. Although a number of the synthesized compounds showed high TSPO binding affinity, these compounds had poor drug-like properties. Further optimization of pharmacokinetic properties of these compounds led to discovery of compound 74, which exhibited anxiolytic effect in the rat Vogel conflict model.

CLAC binds to aggregated Abeta and Abeta fragments, and attenuates fibril elongation.

Deposition of amyloid beta-peptide (Abeta) into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Proteins that codeposit with Abeta are potentially important for the pathogenesis, and a recently discovered plaque-associated protein is the collagenous Alzheimer amyloid plaque component (CLAC). In this study, we investigated the molecular interactions between Abeta aggregates and CLAC using surface plasmon resonance spectroscopy and a solid-phase binding immunoassay. We found that CLAC binds to Abeta with high affinity, that the central region of Abeta is necessary and sufficient for CLAC interaction, and that the aggregation state of Abeta as well as the presence of negatively charged residues is important. We also show that this binding results in a reduced rate of fibril elongation. Taken together, we suggest that CLAC becomes involved at an intermediate stage in the pathogenesis by binding to Abeta fibrils, including fibrils formed from peptides with truncated N- or C-termini, and thereby slows their growth.

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates.

Recently, a novel plaque-associated protein, collagenous Alzheimer amyloid plaque component (CLAC), was identified in brains from patients with Alzheimer's disease. CLAC is derived from a type II transmembrane collagen precursor protein, termed CLAC-P (collagen XXV). The biological function and the contribution of CLAC to the pathogenesis of Alzheimer's disease and plaque formation are unknown. In vitro studies indicate that CLAC binds to fibrillar, but not to monomeric, amyloid beta-peptide (Abeta). Here, we examined the effects of CLAC on Abeta fibrils using assays based on turbidity, thioflavin T binding, sedimentation analysis, and electron microscopy. The incubation of CLAC with preformed Abeta fibrils led to increased turbidity, indicating that larger aggregates were formed. In support of this contention, more Abeta was sedimented in the presence of CLAC, as determined by gel electrophoresis. Moreover, electron microscopy revealed an increased amount of Abeta fibril bundles in samples incubated with CLAC. Importantly, the frequently used thioflavin T-binding assay failed to reveal these effects of CLAC. Digestion with proteinase K or trypsin showed that Abeta fibrils, incubated together with CLAC, were more resistant to proteolytic degradation. Therefore, CLAC assembles Abeta fibrils into fibril bundles that have an increased resistance to proteases. We suggest that CLAC may act in a similar way in vivo.

Characterization of the Alzheimer's disease-associated CLAC protein and identification of an amyloid beta-peptide-binding site.

Amyloid beta-peptide (Abeta) deposition into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Other proteins co-deposit with Abeta in plaques, and one recently identified amyloid-associated protein is the collagen-like Alzheimer amyloid plaque component CLAC. It is not known how CLAC deposition affects Abeta plaque genesis and the progress of the disease. Here, we studied the in vitro properties of CLAC purified from a mammalian expression system. CLAC displays features characteristic of a collagen protein, e.g. it forms a partly protease-resistant triple-helical structure, exhibits an intermediate affinity for heparin, and is glycosylated. Purified CLAC was also used to investigate the interaction between CLAC and Abeta. Using a solid-phase binding assay, we show that CLAC bound with a similar affinity to aggregates formed by Abeta-(1-40) and Abeta-(1-42) and that the interaction was impaired by increasing salt concentrations. An 8-residue-long sequence located in non-collagenous domain 2 of CLAC was found to be crucial for the interaction with Abeta. These findings may be useful for future therapeutic interventions aimed at finding compounds that modulate the binding of CLAC to Abeta deposits.