A phase 3 randomized placebo-controlled trial to assess the efficacy and safety of ipragliflozin as an add-on therapy to metformin in Russian patients with inadequately controlled type 2 diabetes mellitus.

AIM: To assess the efficacy and safety of ipragliflozin as add-on therapy to metformin in Russian patients with type 2 diabetes mellitus. METHODS: In this double-blind study conducted in 14 centers in Russia, 165 patients were randomized 2:1 to ipragliflozin (50 mg/day) or placebo for 24 weeks while continuing metformin. Patients who had HbA1c ≥ 7.0% (53 mmol/mol) at Week 12 received open-label ipragliflozin (50 mg/day) in addition to the blinded drug from Week 12-24. RESULTS: Significant reductions in HbA1c and body weight from baseline to Week 12 in favor of ipragliflozin were observed (adjusted mean difference to placebo: -0.3% (-3 mmol/mol), P = 0.048 and -1.34 kg, P < 0.001, respectively). The incidence of AEs was similar in both groups. Uptitration to 100 mg/day ipragliflozin led to a further reduction in body weight (mean change from Week 12: -0.65 kg, P = 0.004) and an additional 13% (9/69) of patients achieving HbA1c < 7.0% (53 mmol/mol) at Week 24. Incidence of AEs was similar among patients receiving ipragliflozin 50 mg/day (23.7%) and 100 mg/day (24.6%). CONCLUSION: Ipragliflozin 50 mg/day added to metformin significantly reduced HbA1c and body weight after 12 weeks and showed a safety profile comparable to placebo. Uptitration to 100 mg/day improved clinical outcomes with no additional safety concerns.

Pharmacokinetics and safety of fidaxomicin in patients with inflammatory bowel disease and Clostridium difficile infection: an open-label Phase IIIb/IV study (PROFILE).

Objectives: Inflammatory bowel disease (IBD) poses an increased risk for Clostridium difficile infection (CDI). Fidaxomicin has demonstrated non-inferiority to vancomycin for initial clinical cure of CDI in patients without IBD; however, lack of data has caused concerns regarding potential systemic absorption of fidaxomicin in patients with IBD. Methods: The plasma pharmacokinetics (PK) of fidaxomicin and its primary metabolite OP-1118 were evaluated in a multicentre, open-label, single-arm, Phase IIIb/IV study enrolling patients with active IBD and CDI. Patients received fidaxomicin, 200 mg twice daily for 10 days. The primary and secondary endpoints were, respectively, plasma and stool PK of fidaxomicin and OP-1118 on Days 1, 5 and 10 of treatment. Other secondary endpoints included safety of fidaxomicin treatment (assessed until Day 180). ClinicalTrials.gov identifier: NCT02437591. Results: Median Tmax of fidaxomicin and OP-1118 for the PK analysis set (PKAS; 24 patients) was 1-2 h across Days 1, 5 and 10. Cmax ranges were 1.2-154 ng/mL for fidaxomicin and 4.7-555 ng/mL for OP-1118 across Days 1, 5 and 10 (PKAS). The ranges of concentrations in stool were 17.8-2170 µg/g for fidaxomicin and 0-1940 µg/g for OP-1118. Sixty percent (15/25) of patients experienced treatment-emergent adverse events (TEAEs), none of which led to treatment discontinuation or death. Conclusions: Maximum fidaxomicin and OP-1118 plasma concentrations observed in this study population suggest no increase in absorption, compared with patients without IBD. Incidence of TEAEs was similar to previous Phase III trials, suggesting that fidaxomicin is comparatively well tolerated in patients with IBD.

Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives.

BACKGROUND AND OBJECTIVES: Mirabeg ron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC). METHODS: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C max) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed. RESULTS: Mirabegron increased digoxin AUC and Cmax by 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the C max ratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and C max by 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end. CONCLUSIONS: No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.

Bladder wall thickness in women with symptoms of overactive bladder and detrusor overactivity: Results from the randomised, placebo-controlled shrink study.

AIMS: Measurement of bladder wall thickness (BWT) by transvaginal ultrasound (TVUS) may be a less invasive method to diagnose overactive bladder (OAB) or detrusor overactivity (DO) and monitor response to therapy. This study assessed whether treatment with solifenacin affects BWT. METHODS: This was a double-blind, randomised, placebo-controlled, phase 4 study. Adult women with OAB symptoms received solifenacin 5 or 10 mg or placebo once daily for 12 weeks. The co-primary endpoints were change from baseline to Week 12 in TVUS-measured BWT and urinary nerve growth factor. Only results for BWT are presented here. RESULTS: Overall, 547 patients were randomised, 501 patients had a baseline BWT measurement, and change from baseline could be calculated for 478 patients. Mean BWT at baseline was 5.08 mm (range 2.2-11.1, SD = 1.14) and was normally distributed. A significant reduction in BWT from baseline to 12 weeks versus placebo was observed with solifenacin 5 mg (-0.42 vs. -0.16 mm, P = 0.03), but not with the 10 mg dose or with pooled solifenacin, considered the primary comparison. Both solifenacin doses were associated with improvements in efficacy and patient satisfaction endpoints versus placebo. Solifenacin was well tolerated, with dry mouth being the most common adverse event. CONCLUSIONS: There was no consistent effect of solifenacin on BWT in women with OAB/DO, despite improvements in efficacy endpoints. This study suggests that routine clinical assessment of BWT with TVUS for monitoring the effects of OAB/DO treatment is not clinically useful. Neurourol. Urodynam. 35:819-825, 2016. © 2015 Wiley Periodicals, Inc.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

OBJECTIVE: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. MATERIALS AND METHODS: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. RESULTS: Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(∞) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. CONCLUSIONS: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.

The effect of mirabegron, a potent and selective ß3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

Mirabegron is a potent and selective ß3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).

Randomised, multicentre, placebo-controlled, double-blind crossover study investigating the effect of solifenacin and oxybutynin in elderly people with mild cognitive impairment: the SENIOR study.

BACKGROUND: Compared with younger people, the elderly are more likely to suffer from overactive bladder (OAB) and to have other chronic conditions that affect physical or cognitive function. Despite this, there are few data on the cognitive safety of antimuscarinic agents in older patients and none that examine the effect of these agents on those with mild cognitive impairment (MCI). OBJECTIVE: To evaluate cognitive effects during chronic stable dosing with solifenacin and oxybutynin versus placebo in older (≥75 yr) subjects with MCI. DESIGN, SETTING, AND PARTICIPANTS: A randomised, double-blind, triple-crossover trial in 26 elderly volunteers with MCI. Cognitive function was assessed using Cognitive Drug Research (CDR) computerised testing. INTERVENTION: Three treatment periods of 21 d each with solifenacin 5mg once daily, oxybutynin 5mg twice daily, or placebo, separated by 21-d washout periods. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was change from baseline in cognitive function with solifenacin at 6h postdose and oxybutynin at 2h postdose (time points close to their predicted time to peak concentration). Secondary end points included change in cognitive function at additional time points, and safety and tolerability assessments. RESULTS AND LIMITATIONS: Neither agent was associated with significant changes from baseline in any of the five standard, composite outcomes of cognitive function (power of attention, continuity of attention, quality of working memory, quality of episodic memory, and speed of memory). In a secondary analysis, oxybutynin was associated with significant decreases in power and continuity of attention versus placebo at 1-2h postdose. Both agents were well tolerated, with the most frequently reported adverse event being mild or moderate dry mouth. CONCLUSIONS: Solifenacin had no detectable effect on cognition in this group of elderly people with MCI.

Evaluation of the Pharmacokinetic Interaction Between the ß3 -Adrenoceptor Agonist Mirabegron and the Muscarinic Receptor Antagonist Solifenacin In Healthy Subjects.

Mirabegron, a selective ß3 -adrenoceptor agonist, is approved for the treatment of overactive bladder (OAB). Solifenacin is a muscarinic receptor antagonist widely used in the treatment of OAB. This open-label, 1-sequence, 2-arm study investigated whether any pharmacokinetic interaction exists between mirabegron and solifenacin. In arm 1, 21 healthy men and women received 10 mg solifenacin succinate alone and in combination with mirabegron 100 mg qd. In arm 2, 20 healthy men and women received 100 mg mirabegron alone and in combination with solifenacin succinate 10 mg qd. Plasma samples were collected and tolerability was assessed. Following coadministration of mirabegron and solifenacin in arm 1, solifenacin geometric mean ratios (90% confidence interval [CI]) for Cmax and AUCinf were 1.23 (1.15, 1.31) and 1.26 (1.17, 1.35), respectively, compared with solifenacin alone, with a 1.07-fold increase in mean t1/2 . In arm 2, mirabegron ratios (90% CI) for Cmax and AUCinf were 0.99 (0.78, 1.26) and 1.15 (1.01, 1.30), respectively, for the combination relative to mirabegron alone, with an increase in mean tmax of approximately 1 hour. Mirabegron or solifenacin alone or in combination was generally well tolerated.

Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg.

OBJECTIVES: To assess the cognitive effects of single doses of solifenacin 10 mg compared with placebo (primary objective) and oxybutynin immediate release (IR) 10 mg (secondary objective) in elderly subjects. METHODS: Single-centre, randomised, double-blind, placebo-controlled study in 12 healthy elderly volunteers, with three crossover periods separated by two 14-day washout periods. Each sequence consisted of a single dose of solifenacin 10 mg in one period, oxybutynin IR 10 mg in another and placebo in another. Aspects of attention, information processing, working memory, episodic memory and self-rated mood and alertness were tested using the validated Cognitive Drug Research computerised assessment system. RESULTS: There was no evidence from absolute mean values or changes from baseline to suggest that solifenacin 10 mg impaired cognition or self-ratings of mood and alertness versus placebo. Post-hoc ANCOVA showed no statistically significant cognitive deterioration with solifenacin versus placebo, when measured at a time point closest to the probable C(max) of solifenacin. Oxybutynin was associated with statistically significant impairments in several measures of cognitive function at a time point corresponding with its probable C(max). CONCLUSION: In this pilot study, single 10 mg doses of solifenacin did not show any clear propensity to impair cognitive function in a healthy elderly population.