Enhanced Production of EPA-Derived Anti-Inflammatory Metabolites after Oral Administration of a Novel Self-Emulsifying Highly Purified EPA Ethyl Ester Formulation (MND-2119).

AIMS: MND-2119 is a novel once-daily dose self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) and is approved as an antihyperlipidemia agent in Japan. It has improved absorption and achieves higher plasma EPA concentrations at Cmax than conventional EPA-E. In the JELIS trial, concomitant use of EPA-E with statin therapy significantly reduced atherosclerotic cardiovascular disease (ASCVD) risks. As a potential mechanism of action of EPA, endogenous formation of EPA-derived anti-inflammatory metabolites is receiving greater attention. This study aims to investigate the endogenous formation of EPA-derived anti-inflammatory metabolites following single and multiple administrations of MND-2119. METHODS: Healthy adult male subjects were randomly assigned to a nonintervention (control) group, MND-2119 2-g/day group, MND-2119 4-g/day group, or EPA-E 1.8-g/day group for 7 days (N=8 per group). Plasma fatty acids and EPA-derived metabolites were evaluated. Peripheral blood neutrophils were isolated, and the production of EPA-derived metabolites from in vitro stimulated neutrophils was evaluated. RESULTS: After single and multiple administrations of MND-2119 2 g/day, there were significant increases in plasma EPA concentration, 18-hydroxyeicosapentaenoic acid (18-HEPE), and 17,18-epoxyeicosatetraenoic acid compared with those of EPA-E 1.8 g/day. They were further increased with MND-2119 4 g/day administration. In neutrophils, the EPA concentration in the MND-2119 2-g/day group was significantly higher compared with that in the EPA-E 1.8-g/day group after multiple administration, and 18-HEPE production was positively correlated with EPA concentration. No safety issues were noted. CONCLUSIONS: These results demonstrate that MND-2119 increases the plasma and cellular concentrations of EPA and EPA-derived metabolites to a greater extent than conventional EPA-E formulations.

Efficacy, safety, and pharmacokinetics of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension.

Treprostinil is a chemically stable analog of prostacyclin, and inhaled treprostinil was developed to deliver the effects directly to the pulmonary vasculature while minimizing systemic side effects. The objective of the study was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension (PAH). Inhaled treprostinil was administered at three breaths (18 µg)/session four times daily, and the dose was gradually increased to a maximum of nine breaths (54 µg)/session. Endpoints included change in pulmonary vascular resistance index (PVRI) as primary, other efficacy parameters, safety, and PK. Seventeen PAH patients, the majority of whom (76.5%) had been receiving both an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor/soluble guanylate cyclase (sGC) stimulator, received inhaled treprostinil. At Week 12, PVRI statistically decreased by -39.4 ± 25.5% (95% confidence interval: -52.6 to -26.3). The most frequently reported adverse events related to treprostinil were headache, cough, throat irritation, and hot flush. Regarding PK, there were no notable differences in the geometric mean C max and AUClast between Japanese and non-Japanese patients. Treatment with inhaled treprostinil using the dosing regimen approved in the United States resulted in significant improvement in hemodynamics, exercise capacity, and symptoms with a favorable tolerability and safety profile in Japanese patients. Inhaled treprostinil could be a valuable therapeutic option for Japanese patients with PAH, including those receiving a combination therapy with an ERA and a PDE5 inhibitor/sGC stimulator. Trial registration: JAPIC Clinical Trials Information [JapicCTI-194651].

A multicenter, randomized, placebo-controlled, double-blind, comparative study of dienogest at 1 mg/day in patients with primary and secondary dysmenorrhea.

OBJECTIVE: To evaluate the efficacy and safety of dienogest (DNG), a progestational 19-norsteroid, in patients with primary and secondary dysmenorrhea. DESIGN: Phase III, randomized, double-blind, multicenter, placebo-controlled study. SETTING: Clinical study sites in Japan. PATIENT(S): Ninety-four women with dysmenorrhea. INTERVENTION(S): Random assignment to receive DNG (1 mg/day, orally) or placebo for 12 weeks; patients treated for anemia before randomization in cases of complicated anemia. MAIN OUTCOME MEASURE(S): Change in the dysmenorrhea score from baseline to week 12 of treatment with visual analog scale used for pain assessment. RESULT(S): The DNG group was superior to the placebo group in terms of the change from baseline in the dysmenorrhea score at week 12 of treatment in patients with dysmenorrhea. In both primary and secondary dysmenorrhea, the DNG group was superior to the placebo group for each diagnostic category. The mean serum estradiol concentrations were similar between the DNG and the placebo groups. Although the incidence of irregular uterine bleeding was higher in the DNG group, there were no severe or serious events. Most events of genital bleeding were spotting or breakthrough bleeding, suggesting DNG was well tolerated. CONCLUSION(S): In both primary and secondary dysmenorrhea, DNG at 1 mg/day relieved pain and was well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-173547(en).

A clinical pharmacology study of the novel, selective urate reabsorption inhibitor dotinurad in outpatients.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor (SURI), which reduces serum uric acid levels by selective inhibition of the urate transporter 1 (URAT1). The Japanese guideline for the management of hyperuricemia and gout recommends that drug selection should be based on classification of hyperuricemia as a fundamental principle. However, there may be some cases where this principle is not observed. We investigated the pharmacodynamics and safety of dotinurad in outpatients with uric acid overproduction or uric acid underexcretion type. METHODS: This was a multicenter, open-label, forced titration study. Patients were classified as uric acid overproduction or underexcretion type. Study treatment was initiated at 0.5 mg/day, followed by dose titration to the estimated maximum dose of 4 mg/day over 14 weeks. The primary endpoint was urinary uric acid excretion at each 24-h urine collection. RESULTS: A total of 26 hyperuricemic patients with or without gout were enrolled in the study and assigned to the uric acid overproduction group (overproduction group) or the uric acid underexcretion group (underexcretion group). Although urinary uric acid excretion, the primary endpoint, tended to be slightly greater in the overproduction group, no notable difference was noted between the two hyperuricemic types. Neither type had noteworthy safety concerns associated with dotinurad. CONCLUSION: The results of the study demonstrated no relevant differences between the hyperuricemic types in terms of pharmacodynamic action and safety of dotinurad.

Long-term use of dienogest for the treatment of primary and secondary dysmenorrhea.

AIM: To investigate the safety and efficacy of dienogest (DNG), a progestational 19-norsteroid, administered for 52 weeks in patients with primary and secondary dysmenorrhea. METHODS: A total of 147 patients with dysmenorrhea received 1 mg of DNG orally each day for 52 weeks. The dose could be increased to 2 mg/day at or after Week 12 according to the investigator's determination. The primary safety endpoint was evaluation of adverse events, and the secondary safety endpoint was evaluation of adverse drug reactions. The number of days and severity of genital bleeding were assessed according to records in the patients' diary. Lower abdominal pain and/or low back pain because of dysmenorrhea were assessed according to the dysmenorrhea score. RESULTS: The most frequent adverse drug reaction was irregular uterine bleeding (94.6%). Most subjects completed the 52-week administration. Genital bleeding was more likely to occur in subjects with secondary dysmenorrhea than in those with primary dysmenorrhea, and in subjects with "uterine myoma or adenomyosis" than in those with "endometriosis alone." In any of the categorizations, there tended to be fewer days with genital bleeding as the treatment period increased in length, and most of the genital bleeding cases were mild. The change from baseline in the dysmenorrhea score (mean ± standard deviation [SD]) was -3.7 ± 1.6 at Week 24 of treatment and -4.0 ± 1.3 at Week 52. CONCLUSION: This study showed favorable tolerability of the long-term use of DNG to patients with dysmenorrhea and a sustainable pain relief effect.

A non-inferiority study of the novel selective urate reabsorption inhibitor dotinurad versus febuxostat in hyperuricemic patients with or without gout.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. RESULTS: A total of 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was - 2.17% (two-sided 95% confidence interval - 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (- 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. CONCLUSION: The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose.

Evaluation of the efficacy, safety, and clinically recommended dose of dienogest in the treatment of primary dysmenorrhea: a randomized, double-blind, multicenter, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy, safety, and clinically recommended dose of dienogest (DNG; 0.5 mg/d, 1 mg/d, and 2 mg/d) in the treatment of primary dysmenorrhea. DESIGN: A phase II, randomized, double-blind, multicenter, placebo-controlled study. SETTING: Twenty study sites. PATIENTS: A total of 235 patients with primary dysmenorrhea. INTERVENTION(S): Patients were randomized to receive orally a placebo, DNG (0.5 mg/d, 1 mg/d, or 2 mg/d) or ethinylestradiol 0.02 mg/drospirenone 3 mg (an open-label reference drug) for 12 weeks. MAIN OUTCOME MEASURE(S): The primary endpoint was the change from baseline in the dysmenorrhea score at week 12 of treatment. The secondary endpoint was the change from baseline in the visual analogue scale at week 12 of treatment. Subjects were assessed for lower abdominal pain and/or low back pain. RESULTS: All DNG arms were superior to the placebo arm in terms of the change from baseline in the dysmenorrhea score. The results suggest an equal or greater effect of DNG 1 and 2 mg/d in relieving pain, when compared to the reference drug. In the safety profile of DNG, including irregular uterine bleeding, there was no obvious difference among the doses of DNG. A significant decrease in the serum estradiol concentration compared to that in the placebo arm was not observed in the DNG 1 mg/d arm but was observed in the DNG 2 mg/d arm. CONCLUSION(S): The results suggest that DNG at a dose of 1 mg/d is an effective and well-tolerated treatment for primary dysmenorrhea. TRIAL REGISTRATION: JapicCTI-152977 (en).