VONOPRAZAN IS EFFICACIOUS FOR TREATMENT OF HEARTBURN IN NON-EROSIVE REFLUX DISEASE: A RANDOMIZED TRIAL.

BACKGROUND & AIMS: Potassium-competitive acid blockers have documented efficacy for erosive esophagitis. We performed a randomized trial in U.S. subjects diagnosed with non-erosive reflux disease (NERD) of vonoprazan vs. placebo for 4 weeks followed by a 20-week active-treatment extension. METHODS: Adult subjects with heartburn ≥4 days/week during screening without erosive esophagitis on endoscopy were randomized to placebo, vonoprazan 10mg, or vonoprazan 20mg. After 4 weeks, subjects on placebo were re-randomized to vonoprazan 10 or 20mg and those already on vonoprazan continued at the same dose for 20 weeks. Electronic diaries were completed twice daily. The primary endpoint was percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days). RESULTS: Among 772 randomized subjects, the percentage of 24-hour heartburn-free days was 27.7% for placebo vs. 44.8% for vonoprazan 10mg (least squares mean difference=17.1%, p<0.0001) and 44.4% for vonoprazan 20mg (least squares mean difference=16.7%, p<0.0001). Differences in percentage of subjects with a 24-hour heartburn-free day for vonoprazan 10mg vs. placebo and vonoprazan 20mg vs. placebo were 8.3% and 11.6% on day 1 and 18.1% and 23.2% on day 2. The mean/median percentages of 24-hour heartburn-free days over the extension period were similar across the four study arms: 61-63%/76-79%. CONCLUSIONS: Vonoprazan reduced heartburn symptoms in subjects diagnosed with NERD, with the benefit appearing to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. The two vonoprazan doses (10 and 20mg) were similar in efficacy. (ClinicalTrials.gov:NCT05195528).

Randomised clinical trial: Efficacy and safety of on-demand vonoprazan versus placebo for non-erosive reflux disease.

BACKGROUND: Non-erosive reflux disease (NERD) symptoms are often episodic, making on-demand treatment an attractive treatment approach. AIMS: We compared the efficacy and safety of on-demand vonoprazan versus placebo in patients with NERD. METHODS: Patients with NERD, defined as heartburn for ≥6 months and for ≥4/7 consecutive days with normal endoscopy, received once-daily vonoprazan 20 mg during a 4-week run-in period. Patients without heartburn during the last 7 days and with ≥80% study drug and diary compliance were randomised 1:1:1:1 to vonoprazan 10, 20, 40 mg or placebo on-demand for 6 weeks. The primary endpoint was the percentage of evaluable heartburn episodes completely relieved within 3 h of on-demand dosing and sustained for 24 h. RESULTS: Of 458 patients in the run-in period, 207 entered the on-demand period. In the vonoprazan 10 mg group, 56.0% (201/359) of evaluable heartburn episodes met the criteria for complete and sustained relief; 60.6% (198/327) in the 20 mg group; and 70.0% (226/323) in the 40 mg group, compared with 27.3% (101/370) in the placebo group (p < 0.0001 versus placebo for each vonoprazan group). By 1 h post-dose, vonoprazan was associated with complete relief of significantly more heartburn episodes compared with placebo. No serious treatment-emergent adverse events were reported. CONCLUSION: On-demand vonoprazan may be a potential alternative to continued daily acid suppression therapy for the relief of episodic heartburn in patients with NERD. CLINICALTRIALS: gov: NCT04799158.

Tiered approach to evaluate the CYP3A victim and perpetrator drug-drug interaction potential for vonoprazan using PBPK modeling and clinical data to inform labeling.

Vonoprazan is metabolized extensively through CYP3A and is an in vitro time-dependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug-drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically-based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug- and system-specific parameters, and clinical data and observations from a [14 C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time-dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co-administration with moderate and strong CYP3A inducers should be avoided.

Rates of Antimicrobial Resistance in Helicobacter pylori Isolates From Clinical Trial Patients Across the US and Europe.

INTRODUCTION: Guidelines recommend that proton pump inhibitor-based triple regimens with clarithromycin not be used for Helicobacter pylori infection in areas where clarithromycin resistance is ≥15%, or in patients with prior macrolide use. Up-to-date information on local resistance patterns is limited, especially in the US. Here, we report resistance rates to antibiotics commonly used to treat H. pylori from a large study conducted in the US and Europe (pHalcon-HP). METHODS: Gastric mucosal biopsies were collected from adult participants with H. pylori infection during screening. Minimum inhibitory concentrations were determined via agar dilution for clarithromycin, amoxicillin, and metronidazole, with breakpoints ≥1 µg/mL, >0.125 µg/mL, and >8 µg/mL, respectively. Resistance rates were obtained for the US and Europe, and also for US subregions and participating European countries. RESULTS: Resistance rates were established in isolates from 907 participants. Overall, 22.2% were resistant to clarithromycin, 1.2% to amoxicillin, and 69.2% to metronidazole. Resistance in the US and Europe was similar; metronidazole resistance was the most prevalent (50%-79%) and amoxicillin the least (≤5%). In all subregions, ≥15% of isolates were resistant to clarithromycin, except the UK (0/8 isolates). Among clarithromycin-resistant isolates, 75% were also metronidazole-resistant. Two US isolates were resistant to clarithromycin and amoxicillin; one of these was also metronidazole-resistant. DISCUSSION: The resistance rates observed in this study argue against the continued empiric use of proton pump inhibitor-based triple therapy containing clarithromycin, per treatment guidelines, and highlight the need for antibiotic resistance surveillance and novel treatment strategies for H. pylori infection in the US and Europe.

Pharmacodynamics and Pharmacokinetics of the Potassium-Competitive Acid Blocker Vonoprazan and the Proton Pump Inhibitor Lansoprazole in US Subjects.

INTRODUCTION: We assessed pharmacodynamics and pharmacokinetics of a potassium-competitive acid blocker and proton pump inhibitor in US subjects. METHODS: Healthy adults were randomized to 7-day periods of vonoprazan 20 mg once daily followed by lansoprazole 30 mg once daily or the reverse order, separated by ≥ 7 days of washout. RESULTS: Vonoprazan (N = 40) had higher proportions of 24-hour periods with intragastric pH > 4 than lansoprazole (N = 41,38) on day 1 (62.4% vs 22.6%, P < 0.0001) and day 7 (87.8% vs 42.3%, P < 0.0001). Separation in pH started ∼2.5 hours after the first dose. DISCUSSION: Vonoprazan provided more rapid and potent inhibition of intragastric acidity than lansoprazole in US subjects.

A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure.

Vonoprazan, a potassium-competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed-effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non-Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non-Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non-Asian populations.

Correction to: Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

In the original publication of the article, the ALT and AST values in Fig. 5a-e were capped at 10× ULN, which did not accurately reflect the narrative provided for each case. In this correction, the original Fig. 5a-e (Fig. 1a-e) and the correct Fig. 5a-5e (Fig. 2a-e) are published.

Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

INTRODUCTION: Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. METHODS: The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. RESULTS: The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases. CONCLUSIONS: Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia.

BACKGROUND: In most cases of hyponatremia, arginine vasopressin secretion is inappropriately high. This placebo-controlled, randomized, double-blind multicenter study evaluated the efficacy and safety of oral conivaptan, a V1A/V2-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia. METHODS: Eighty-three patients with serum [Na] less than 130 mEq/L were stratified by volume status and randomly assigned to placebo or conivaptan 40 or 80 mg/d for 5 days. RESULTS: Conivaptan increased the baseline-adjusted area under the serum [Na]-time curve significantly more than placebo (P = 0.0001). Patients given either dose of conivaptan demonstrated a serum [Na] of 4 mEq/L or greater above baseline significantly faster than those given placebo (P < 0.001) and maintained that increase for a greater total time (P = 0.0001). The least squares mean change in serum [Na] from baseline to end of treatment was also significantly greater with conivaptan 40 and 80 mg/d (6.8 and 8.8 mEq/L, respectively) (P = 0.0001) than that with placebo (1.2 mEq/L). The percentage of patients who obtained an increase from baseline in serum [Na] of 6 mEq/L or greater or normal serum [Na] was significantly higher among patients given conivaptan 40 and 80 mg/d (67% and 88%, respectively) than among those given placebo (20%; P < 0.001). Conivaptan was well tolerated; the most frequent adverse events were urinary tract infection, anemia, pyrexia, cardiac failure, hypotension, and hypokalemia. CONCLUSION: Oral conivaptan was effective in increasing serum [Na] in patients with euvolemic or hypervolemic hyponatremia and had a favorable safety profile.

Efficacy and safety of solifenacin succinate 10 mg once Daily: A multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group trial in patients with overactive bladder.

BACKGROUND: Solifenacin succinate is an antimuscarinic drug with reported efficacy and tolerability at a recommended starting dose of 5 mg QD in patients with overactive bladder (OAB). OBJECTIVE: The objective of this trial was to investigate the efficacy, safety, and tolerability of solifenacin 10 mg QD in patients with OAB. METHODS: In this multicenter, Phase III, double-blind, placebo-controlled, parallel-group trial, patients aged ≥18 years with OAB were randomized at a 1:1 ratio to receive solifenacin 10 mg or placebo QD for 12 weeks. The patients were instructed to complete a micturition diary for the 3 days preceding each scheduled visit (weeks 4, 8, and 12). The primary end point was the change from baseline in the mean number of micturitions per 24 hours; secondary end points included the mean change from baseline in the number of episodes per 24 hours of urgency, incontinence, nocturnal voiding, and nocturia and the mean volume voided per micturition. Tolerability was monitored through adverse events (AEs), vital sign measurements, ECGs, laboratory assessments, and physical examination. RESULTS: A total of 672 patients were randomized and received ≥1 dose of study drug (solifenacin, n = 340; placebo, n = 332). The mean (SE) decrease from baseline to study end in the number of micturitions per 24 hours was significantly greater in the solifenacin group compared with the placebo group (-3.0 [0.2] vs -1.5 [0.2], respectively; P < 0.001). The mean decrease in the number of episodes of incontinence was significantly greater in the solifenacin group compared with the placebo group (-2.0 [0.2] vs -1.1 [0.2]; P < 0.001), as was the mean decrease in the number of episodes of urgency (-4.1 [0.2] vs -2.1 [0.2]; P < 0.001). Of the patients with ≥1 incontinence episode per 24 hours at baseline, significantly more patients in the solifenacin group achieved complete continence at study end than did patients in the placebo group (119/225 [52.9%] vs 80/237 [33.8%]; P < 0.001). The change from baseline to study end in the mean volume voided per micturition increased significantly in the solifenacin group compared with the placebo group (47.2 vs 2.7 mL; P < 0.001). Most AEs were mild or moderate in intensity. The AEs that were most commonly reported in the solifenacin-treated group were anticholinergic in nature: dry mouth (91 [26.8%] vs 13 patients [3.9%] in the placebo group; P < 0.001); constipation (58 [17.1%] vs 11 [3.3%]; P < 0.001); and blurred vision (12 [3.5%] vs 4 [1.2%]; P < 0.05). Serious AEs (SAEs) were reported for 5 patients in the solifenacin group and 3 patients in the placebo group. In the solifenacin group, 2 patients experienced chest pain, 1 had cellulitis, 1 had dehydration, and 1 had colonic obstruction; only 1 SAE (colonic obstruction) was judged to be possibly related to the study drug. In the placebo group, 1 patient had chest pain, 1 had bacterial meningitis, and 1 had hemopericardium. CONCLUSIONS: This study found that solifenacin 10 mg QD for 12 weeks was associated with significantly reduced symptoms of OAB, including the frequency of micturition, and episodes of urgency and of incontinence. With solifenacin, the volume voided per micturition increased by 47.2 mL, and 53% of patients with ≥1 incontinence episode per 24 hours at baseline achieved complete continence. This efficacy was accompanied by a favorable safety and tolerability profile.

Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study.

OBJECTIVE AND DESIGN: Most cases of euvolaemic hyponatraemia are associated with elevated plasma levels of AVP. Conivaptan is a high-affinity, nonpeptide vasopressin V(1A)/V(2)-receptor antagonist. We performed a subgroup analysis of a multicentre, randomized, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of intravenous (i.v.) conivaptan for the treatment of euvolaemic hyponatraemia. PATIENTS: Fifty-six euvolaemic patients with serum [Na(+)] of 115 to < 130 mmol/l received conivaptan 40 or 80 mg/day or placebo via continuous i.v. infusion for 4 days. A 20-mg loading dose was administered intravenously over 30 min in the conivaptan groups; the placebo group received a placebo loading dose. MEASUREMENTS: Change in serum [Na(+)], measured by the baseline-adjusted area under the serum [Na(+)]-time curve (AUC), was the primary efficacy parameter. Secondary efficacy measures included the time from the first dose to a confirmed > or = 4 mmol/l increase in serum [Na(+)], total time with serum [Na(+)] > or = 4 mmol/l above baseline, change in serum [Na(+)] from baseline, and number of patients with a confirmed > or = 6 mmol/l increase in serum [Na(+)] or normal [Na(+)]. Safety assessments included adverse events (AE), incidence of overly rapid correction of serum [Na(+)], and changes in vital signs and electrocardiographic and clinical laboratory parameters. RESULTS: During the first 2 days of treatment, and over the entire 4-day treatment period, both conivaptan doses significantly increased the serum [Na(+)] AUC more than placebo (P < 0.01). Conivaptan 40 and 80 mg/day significantly improved all secondary efficacy measures. Conivaptan was generally well tolerated; infusion-site reaction was the most common AE. CONCLUSIONS: In hospitalized patients with euvolaemic hyponatraemia, i.v. conivaptan significantly increased serum [Na(+)] promptly and was well tolerated.

Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.

BACKGROUND: Most cases of hyponatremia--serum sodium concentration ([Na+]) < 135 mEq/l (< 135 mM)--are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V1A/V2-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. METHODS: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na+] 115 to < 130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na+], measured by the baseline-adjusted area under the [Na+]-time curve. The secondary measures included time from first dose to a confirmed > or = 4 mEq/l serum [Na+] increase, total time patients had serum [Na+] > or = 4 mEq/l higher than baseline, change in serum [Na+] from baseline to the end of treatment, and number of patients with a confirmed > or = 6 mEq/l increase in serum [Na+] or normal [Na+] (> or = 135 mEq/l). RESULTS: Both conivaptan doses increased area under the [Na+]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean +/- standard error serum [Na+] increase associated with placebo was 0.8 +/- 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 +/- 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 +/- 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. CONCLUSION: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na+] and was well tolerated.

Intravenous conivaptan: effects on the QTc interval and other electrocardiographic parameters in healthy volunteers.

Prolongation of the QT interval is clinically important because it may be associated with torsade de pointes, a potentially fatal arrhythmia. The objective of this study was to define the effects on electrocardiogram (ECG) of intravenous conivaptan, the first arginine vasopressin V1A/V2-receptor antagonist indicated for the treatment of euvolemic hyponatremia, on hospitalized patients without congestive heart failure. After a placebo run-in period, participants in this randomized, single-blind, placebo- and positive-controlled, parallel-group study received an intravenous 20-mg loading dose of conivaptan (day 1), followed by a 40-mg/d continuous infusion (days 1-4); a 20-mg loading dose of conivaptan (day 1), followed by an 80-mg/d continuous infusion (days 1-4); or moxifloxacin 400 mg (positive control) or placebo from day 1 to day 4. The primary ECG endpoint was QTc interval duration, which was determined by the individually corrected QT interval for each subset; secondary endpoints included QT intervals corrected with Bazett's formula and Fridericia's formula. No clinically notable changes in ECG parameters were associated with conivaptan, suggesting that conivaptan did not affect cardiac repolarization or cardiac conduction.

Solifenacin treatment for overactive bladder in black patients: patient-reported symptom bother and health-related quality of life outcomes.

OBJECTIVE: Health-related quality of life (HRQoL) data for black patients receiving overactive bladder (OAB) treatment have not been previously reported. This study presents patient-reported outcomes, measured by symptom bother and HRQoL, in black patients participating in an open-label study of solifenacin succinate. Results are presented, as are those from the full study population. METHODS: In the 12 week, VESIcare Open-Label Trial (VOLT), patients received solifenacin 5 mg or 10 mg once daily according to an individualized, flexible dosing regimen. A post-hoc analysis assessed solifenacin efficacy and safety in blacks (n = 274). Three patient derived indices served as study endpoints. The Patient Perception of Bladder Condition (PPBC) scale assessed overall symptom bother, a visual analog scale (VAS) recorded individual symptom bother, the Overactive Bladder Questionnaire (OAB-q) measured OAB related HRQoL. RESULTS: Blacks reported significant reductions in bladder related problems based on PPBC scores (p < 0.001) and improvements in all OAB-q subscales (symptom severity, coping, concern, sleep, social, and HRQoL; p < 0.001). Based on VAS ratings, significant improvements were reported for urinary urgency, urge incontinence, frequency, and nocturia (p < 0.001 for change from baseline). Although this study was not placebo-controlled and statistical comparisons were not made, results were similar in the full study population. In total, 46% of black patients experienced adverse events (mostly anticholinergic) and 7.6% discontinued treatment as a result. CONCLUSIONS: Solifenacin treatment was perceived as offering relief from symptom bother and improving HRQoL in the black cohort from VOLT. These results are similar to those in the full VOLT population.

Solifenacin for overactive bladder with incontinence: symptom bother and health-related quality of life outcomes.

BACKGROUND: Approximately one-third of patients with overactive bladder (OAB) experience incontinence, a bothersome symptom with a clear negative effect on quality of life. OBJECTIVE: To assess OAB patients' perceptions of improvements in symptom bother and quality of life after taking solifenacin under conditions reflecting day-to-day practice. METHODS: VOLT (the VESIcare Open-Label Trial) was a prospective, open-label study in patients with OAB (defined as urgency, urge urinary incontinence, daytime frequency, or nocturia for > or =3 mo) who were treated with flexibly dosed, once-daily solifenacin for 12 weeks. This study included subjects enrolled in VOLT who, at baseline, had urge incontinence and reported incontinence as their most bothersome symptom. All patients were started on solifenacin 5 mg/day; at week 4, the dosage could be increased to 10 mg/day and at week 8 could be maintained or decreased back to 5 mg/day. Efficacy was assessed by 3 independent patient-reported outcomes: the Patient Perception of Bladder Condition (PPBC) scale, a visual analog scale (VAS) for assessing individual symptoms, and the Overactive Bladder Questionnaire (OAB-q). RESULTS: Of the 2205 patients in the VOLT full analysis set, 1586 (71.9%) had urge incontinence at baseline, of which 582 (36.7%) reported incontinence as their most bothersome symptom. In this cohort, mean PPBC score at baseline was 4.6 (indicating moderate-to-severe problems) and at endpoint had decreased significantly to 2.9 (very minor to some minor problems; p < 0.001). At endpoint, 80.4% of patients achieved improvement in their PPBC score. These patients reported significant improvements from baseline in urinary urgency, urge incontinence, frequency, and nocturia on the VAS (p < 0.001) and all OAB-q domains (symptom severity, coping, concern, sleep, social, health-related quality of life) at endpoint (p < 0.001). CONCLUSIONS: Patients reporting urge incontinence as their most bothersome OAB symptom can be expected to demonstrate significant improvements in multiple patient-related outcomes following treatment with flexibly dosed solifenacin.

Pharmacokinetics, safety, and tolerability of solifenacin in patients with renal insufficiency.

To evaluate the pharmacokinetics, safety, and tolerability of solifenacin in patients with mild, moderate, or severe renal disease, eighteen patients with renal disease and six healthy volunteers received a single oral dose of solifenacin (10 mg). Pharmacokinetic parameters were assessed from blood samples drawn over a 360-h period. Safety and tolerability were also evaluated. Total mean +/- S.D. exposure (ng . h/mL) to solifenacin in healthy individuals (1190 +/- 403) was increased in patients with renal disease (mild: 1784 +/- 792, moderate: 1559 +/- 555, severe: 2530 +/- 700), and elimination half-life (mean +/- S.D. [h]) was prolonged (healthy: 68.2 +/- 27.2, mild: 89.1 +/- 34.5, moderate: 90.6 +/- 27.3, severe: 111 +/- 38.3). A significant correlation was found between creatinine clearance and pharmacokinetic parameters for exposure and apparent oral clearance. No deaths or serious adverse events occurred during the study. Solifenacin 10 mg was well tolerated in patients with renal disease. Solifenacin displays a higher exposure and a prolonged half-life in patients with renal impairment, especially severe. Therefore, while no special cautions are necessary for patients with mild/moderate renal impairment, patients with severe renal impairment should receive no more than 5 mg solifenacin once daily.

Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers.

Solifenacin succinate (YM905) is a new, once-daily, orally administered muscarinic receptor antagonist designed to treat overactive bladder. The metabolism of solifenacin involves hepatic cytochrome P450 (CYP) 3A4; therefore, the pharmacokinetics of solifenacin may be affected by drugs that inhibit CYP3A4. This study aimed to examine the effects of co-administration of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of solifenacin in healthy volunteers. In a single-site, open-label, monosequence, crossover study, 17 healthy men and women aged 18 to 65 years received a single 10 mg oral dose of solifenacin, which is is the highest available dose. After a 14-day wash-out period, they began 20 days of oral ketoconazole at a dose of 200 mg once daily. A single 10 mg dose of solifenacin was administered again on day 7 of ketoconazole treatment. Pharmacokinetics was assessed using the standard measurements of maximum plasma concentration (Cmax), time to Cmax, area under the curve (AUC), and elimination half-life (t1/2). Co-administration of ketoconazole resulted in a 1.43 times increase in the C(max) of solifenacin and an approximately 2 times increase in AUC. The mean t1/2 of solifenacin was extended from 49.3 to 77.5 hr whereas time to Cmax did not change. No substantial increase in the overall rate of adverse events, and no significant effects on vital signs, electrocardiography, clinical laboratory values, or physical examinations were noted. Administration of 200 mg ketoconazole once daily in healthy male volunteers resulted in a 2 times increase in exposure of a single 10 mg dose of solifenacin. Since ketoconazole is one of the strongest inhibitors of CYP3A4, it is expected that co-administration of other CYP3A4 inhibitors will not result in a stronger increase in solifenacin exposure.

Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia.

CONTEXT: Hyponatremia [serum sodium concentration ([Na(+)]), <135 mEq/liter] is the most common fluid and electrolyte abnormality among hospitalized patients. It is frequently caused by the inappropriate release of arginine vasopressin. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of oral conivaptan, a vasopressin V(1A)/V(2) receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia. DESIGN: The study design was a 5-d placebo-controlled, randomized, double-blind study. SETTING: The study was performed at a hospital. INTERVENTION: Oral conivaptan (40 or 80 mg/d) or placebo was given in two divided doses. PATIENTS: Seventy-four patients (average baseline serum [Na(+)], 115 to <130 mEq/liter) were studied. MAIN OUTCOME MEASURE: The main outcome measure was the change from baseline in serum [Na(+)] area under the curve. RESULTS: The least-squares mean change from baseline in the serum [Na(+)] area under the curve with conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) and 2.5-fold (P < 0.001) greater, respectively, than that with placebo. The median time to achieve a confirmed increase in serum [Na(+)] of 4 mEq/liter or more from baseline was 71.7 h for placebo, 27.5 h for 40 mg/d conivaptan (P = 0.044), and 12.1 h for 80 mg/d conivaptan (P = 0.002). The mean total times during which patients had a serum [Na(+)] level of 4 mEq/liter or more above baseline were 46.5, 69.8, and 88.8 h (P = 0.001), respectively. The least-squares mean change in serum [Na(+)] from baseline to end of treatment was 3.4 mEq/liter for placebo, 6.4 mEq/liter for 40 mg/d conivaptan, and 8.2 mEq/liter for 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na(+)] (>/=135 mEq/liter) or increase of 6 mEq/liter or more was observed in 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014). Headache, hypotension, nausea, constipation, and postural hypotension were the most common adverse events. CONCLUSION: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na(+)] in hyponatremia.

Symptom bother and health-related quality of life outcomes following solifenacin treatment for overactive bladder: the VESIcare Open-Label Trial (VOLT).

BACKGROUND: Most clinical trials designed to evaluate overactive bladder (OAB) syndrome treatments have focused on measuring micturition variables from bladder diaries. However, although diaries help physicians assess symptoms objectively, they lack information on patients' subjective experience of OAB symptoms and the effects of treatment. OBJECTIVE: The objective of this study was to assess patients' perceptions of improvements in symptom bother and health-related quality of life (HRQOL) with solifenacin succinate 5- and 10-mg treatments in patients with OAB. METHODS: VOLT (VESIcare Open-Label Trial) was a prospective, flexible-dosing trial performed at 207 centers in the United States. Ambulatory adult (aged > or = 18 years) men and women with an established diagnosis of OAB (urgency, urge urinary incontinence, frequency, and/or nocturia for > or = 3 months) and who provided a sterile urine sample received solifenacin QD for 12 weeks. Initially, all patients received 5 mg/d, with the option of adjustment to 10 mg/d at 4 and 8 weeks. Effectiveness was assessed using the Patient Perception of Bladder Condition (PPBC) scale, a visual analog scale (VAS) for the degree of bother caused by individual OAB symptoms, and the overactive bladder questionnaire (OAB-q). Assessments were performed at study initiation and study end or study termination. Adverse events (AEs) were assessed throughout. RESULTS: Patients (N = 2225) were enrolled between June 2004 and April 2005. Patients with baseline data (n = 2205) had a mean (SD) age of 59.7 (14.4) years; most patients were women (1813 [82.2%]) and white (1761 [79.9%]). Of the total patients enrolled, 1743 (78.3%) completed all 12 weeks of the study. After 12 weeks of solifenacin treatment, improvement was observed in the mean values of patient-reported perception of bladder condition. Significant change was observed on the PPBC scale from the mean baseline value to study end (4.4 vs 2.9; P < 0.001). All subscales of HRQOL significantly improved on the OAB-q score (mean changes, 14.7 to 29.6; all, P < 0.001). On the VAS, there was a significant reduction in the degree of bother associated with urgency, urge urinary incontinence, frequency, and/or nocturia (mean changes in VAS ratings, -36.7 to -41.8; all, P < 0.001 vs baseline). Solifenacin was well tolerated in most patients. Treatment-emergent AEs were reported by 1321 (59.4%) patients. Most reported AEs were anticholinergic in nature and of mild to moderate severity: dry mouth, 477 (21.4%); constipation, 295 (13.3%); headache, 76 (3.4%); blurred vision, 57 (2.6%); nausea, 39 (1.8%); dyspepsia, 34 (1.5%); and dry eye, 29 (1.3%). Two hundred sixteen (9.7%) patients discontinued treatment due to AEs. CONCLUSION: Flexibly dosed solifenacin 5 and 10 mg QD was associated with reductions in patient-reported OAB symptom bother and improvements in patients' perception of bladder condition and HRQOL.