Analysis of the impact on efficacy of lubiprostone dose reduction to manage adverse events in the treatment of chronic constipation in Japan.

OBJECTIVE: To compare outcomes between two doses of lubiprostone in patients with chronic constipation (CC), to assess whether dose reduction affects efficacy. METHODS: This open-label exploratory study involved 146 patients with CC treated initially with lubiprostone 24 mcg twice daily for a planned duration of 4 weeks. Patients who experienced adverse events (AEs) had their dose reduced to 12 mcg twice daily (for 4 weeks). RESULTS: Lubiprostone dose was unchanged in 104 patients and reduced due to AEs in 42 patients. Significant differences in the mean number of bowel movements per week favored the dose-reduced group at Week 1 and end of follow-up. No between-group differences were observed over time for mean number of days per week with bowel movements or mean Bristol Stool Form Scale scores. Symptoms of abdominal bloating, strained defecation, and sensation of incomplete evacuation improved in both groups. Before dose reduction, nausea was reported by 64.3% and diarrhea by 45.2% of patients in the dose-reduced group; after dose reduction, no patients reported nausea and one patient reported diarrhea. CONCLUSION: Dose reduction of lubiprostone reduced the incidence of AEs, with no compromise to efficacy, and may be a suitable approach for patients who develop AEs during treatment.

Comparison of two biosimilarity studies of FKB327 with the adalimumab reference product: randomized phase 1 studies of single-blind, single-dose subcutaneous injection in healthy Japanese male participants.

BACKGROUND: FKB327 has been developed as a biosimilar of the adalimumab reference product (RP). We compared the pharmacokinetics (PK), safety, and immunogenicity of FKB327 with those of the adalimumab RP after a single dose by subcutaneous (SC) injection in Japanese male participants. METHODS: Two randomized, single-blind, single-dose studies were conducted in healthy Japanese male participants to compare PK characteristics between FKB327 and the RP. Study 1 included 130 participants who were randomized in a 1:1 ratio to receive a subcutaneous injection of 40 mg of either FKB327 or the RP into the abdomen. In Study 2, another 130 subjects were randomized in a 1:1 ratio to receive either drug as in Study 1, but the drug administration site was changed to the thigh. The primary PK endpoints of both studies were area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) and maximum serum concentration; area under the concentration-time curve from time zero to 360 h was also evaluated as one of the primary endpoints in Study 1. Biosimilarity in terms of pharmacokinetics was determined if the 90% confidence interval of the mean difference in geometric mean ratio of all primary PK parameters was within the prespecified equivalence criteria (0.80-1.25). Immunogenicity and safety were also evaluated as secondary endpoints. RESULTS: The serum concentration-time profiles were comparable between the FKB327 and the RP treatment groups in both studies. Primary PK parameters were within the prespecified bioequivalence range in Study 2, although AUC0-t was slightly outside the upper side of the range in Study 1. No differences in safety profile were observed in these studies. The incidence of anti-drug antibodies (ADAs) and impact of ADAs on PK profile were similar among the treatment groups in both studies. CONCLUSION: Biosimilarity between FKB327 and the RP after a single 40-mg SC injection was confirmed in healthy Japanese male participants by modifying the study design. TRIAL REGISTRATION: jRCT2071200058 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200058, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200058) and jRCT2071200057 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200057, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200057). Retrospectively registered 25/11/2020.

An assessment of the efficacy and safety of dydrogesterone in women with ovarian endometrioma: An open-label multicenter clinical study.

PURPOSE: To assess the efficacy and safety of dydrogesterone in Japanese women with ovarian endometrioma in a real-world setting. METHODS: The post-marketing study involved 15 sites in Japan. Dydrogesterone 10 mg twice daily orally was administered for 21 days (day 5-25 of each menstrual cycle) for 4 cycles. The primary outcome measure was the change in ovarian endometrioma volume from baseline. Secondary outcome measures included total dysmenorrhea score (0 = absent to 3 = severe), severity of dysmenorrhea pain [0-10cm visual analog scale (VAS)], serum carbohydrate antigen 125 (CA-125) levels, and safety. RESULTS: The study group comprised women with an endometrioma aged 20 to 49 (47.4% cases aged ≥40 years). Endometrioma volume was reduced in 50% (26/52), unchanged in 25% (13/52), and increased in 25% (13/52) of women from baseline to the end of cycle 5; three-quarters of patients thus had either reduced or unchanged ovarian endometrioma volume. Dydrogesterone significantly reduced total dysmenorrhea scores and severity of dysmenorrhea pain VAS during treatment compared with baseline. CA-125 levels were not significantly changed during the study. The incidence of adverse events and adverse drug reactions in 59 subjects was 13.6% and 11.9%. CONCLUSIONS: Dydrogesterone prevented an increase in endometrioma size in many women, and it also significantly improved total dysmenorrhea scores and severity of dysmenorrhea pain, and was well tolerated. The ClinicalTrials.gov identifier of the study was NCT02921763.