Capsule and Sprinkle Formulations of Lubiprostone Are Not Biologically Similar in Patients with Functional Constipation.

INTRODUCTION: Lubiprostone capsules are approved for managing three different chronic constipation conditions. A "sprinkle" formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo. METHODS: A 1-week randomized, placebo-controlled, double-blinded, bioequivalence study (study 302) and a single-dose PK and bioavailability crossover study (study 304) were conducted. In study 302, 522 subjects with chronic constipation were randomized to lubiprostone sprinkle 24 µg twice daily (BID), lubiprostone capsule 24 µg BID, or placebo. The primary efficacy endpoint was observed spontaneous bowel movement (SBM) counts (equivalence defined as showing the 90% confidence interval [CI] of the "between-group SBM ratio" to be contained within 0.8-1.25). Study 304 included two cohorts of healthy volunteers randomized to a single 48-µg lubiprostone dose, sprinkle, or capsule (n = 35) or to a single 48-µg sprinkle dose, in fed or fasted state (n = 14). RESULTS: Both lubiprostone formulations significantly improved SBM count (sprinkle, 4.82 ± 3.66, P = 0.002; capsule, 5.74 ± 3.79, P < 0.0001) vs placebo (3.68 ± 2.16), but equivalent efficacy was not demonstrated, with a 90% CI for the SBM count ratio of 0.69-0.95. Quantifiable PK data on lubiprostone were limited; however, overall exposure to the M3 metabolite was approximately 44% higher with sprinkles vs capsules under fasted conditions (geometric mean ratio 1.441 [90% CI, 1.166, 1.782]), and exposure with the sprinkle formulation was 11% lower in the fed state vs the fasted state (geometric mean ratio 0.888 [90% CI, 0.675, 1.168]). Both formulations were generally well tolerated. CONCLUSION: Despite the significant improvement in SBM counts vs placebo, the sprinkle formulation did not demonstrate bioequivalence to the capsule formulation in either pharmacodynamic or PK key parameters. TRIAL REGISTRATION: Study 302: ClinicalTrials.gov identifier, NCT03097861; https://www.clinicaltrials.gov/ct2/show/NCT03097861 ; Study 304: ClinicalTrials.gov identifier, NCT03010631; https://www.clinicaltrials.gov/ct2/show/NCT03010631 .

A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain.

OBJECTIVES: This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain. METHODS: Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 µg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks. RESULTS: In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone. CONCLUSIONS: Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy.

BACKGROUND & AIMS: The immunosuppressive treatment for autoimmune hepatitis (AIH) patients is prednisone and azathioprine. Ten percent to 20% of patients do not respond or are intolerant of standard treatment. The aim of this study was to assess the biochemical, histologic, and hematologic parameters during mycophenolate mofetil (MMF) treatment in AIH patients who did not respond to or were intolerant of prednisone and/or azathioprine. METHODS: A retrospective study was performed of 15 AIH patients who received MMF either as monotherapy or in combination with prednisone after failure or intolerance of the initial regimen. Records were reviewed as to initial therapy, reasons why MMF was initiated, liver enzyme levels, histology on MMF, and complications. RESULTS: The mean age was 60 +/- 15 years. All patients were started on MMF at 1 gram twice a day, 3 on MMF monotherapy, and 12 on prednisone and MMF. The average MMF treatment duration was 41 months. Alanine aminotransferase levels decreased significantly from 91.73 +/- 88.69 to 60.87 +/- 71.2 (P = .03) on MMF treatment. Inflammatory scores (2.59 +/- 0.97 to 1.14 +/- 1.21, P = .02) and Ishak fibrosis scores (4.10 +/- 1.37 to 2.5 +/- 1.51, P = .02) also decreased. No significant hematologic complications were noted during MMF treatment. CONCLUSIONS: Administration of MMF, either as monotherapy or in combination with prednisone, results in biochemical and histologic improvement in AIH patients who are prednisone and/or azathioprine intolerant or resistant without the development of significant complications. MMF should be studied prospectively as an alternative agent in the treatment of autoimmune liver disease.