Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity.

The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day-1 . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz /F), and terminal half-life (t1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.

Long-term efficacy and safety of solifenacin in pediatric patients aged 6 months to 18 years with neurogenic detrusor overactivity: results from two phase 3 prospective open-label studies.

INTRODUCTION: The standard recommended treatment for neurogenic detrusor overactivity (NDO) is clean intermittent catheterization combined with an antimuscarinic agent. However, the adverse systemic side-effects of oxybutynin, the most widely used agent, are of concern. OBJECTIVE: To evaluate the efficacy and safety of solifenacin in pediatric patients with NDO, aged 6 months-<5 years and 5-<18 years. STUDY DESIGN: Two open-label, baseline-controlled, phase 3 studies were conducted in pediatric patients with NDO. Patients were treated with sequential doses of solifenacin oral suspension (pediatric equivalent doses 2.5-10 mg) for 12 weeks to determine each patient's optimal dose, followed by a fixed dose ≥40-week treatment period. Primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC) after 24 weeks. Secondary endpoints included bladder compliance, bladder volume until first detrusor contraction (>15 cmH2O), number of overactive detrusor contractions (>15 cmH2O), maximum catheterized volume (MCV)/24 h, and incontinence episodes/24 h. Safety parameters were treatment-emergent adverse events (TEAEs), serious adverse events, laboratory variables, vital signs, electrocardiograms, and ocular accommodation and cognitive function assessments. RESULTS: After 24 weeks, MCC had significantly increased compared with baseline in patients aged 6 months -<5 years and 5-<18 years (37.0 ml and 57.2 ml, respectively; P < 0.001; Fig.). Improvement was also observed after 52 weeks' treatment. Significant changes were observed from baseline to week 24 in all secondary endpoints in both age groups: increase in bladder compliance, increase in bladder volume to first detrusor contraction as a percentage of expected bladder capacity, reduction in the number of overactive detrusor contractions, increase in MCV, and decreased incontinence episodes. TEAEs were mostly mild or moderate, and there were no new drug-related TEAEs compared with adult studies. Age-related improvements were noted in ocular accommodation and cognitive function. DISCUSSION: These long-term multicenter investigations demonstrated the efficacy and safety of solifenacin in pediatric patients with NDO. The observed increases in MCC were clinically relevant and demonstrated that an increase in fluid volume can be accommodated in the bladder prior to reaching intravesical pressures that endanger kidney function and/or are associated with leakage or discomfort. Solifenacin was well tolerated with low incidences of constipation and dry mouth (typically associated with antimuscarinics), central nervous system-related side-effects, and facial flushing. CONCLUSION: Solifenacin was effective and well tolerated in pediatric patients with NDO, aged 6 months-<18 years, suggesting that it is a viable alternative to oxybutynin, the current standard of care. STUDIES ARE REGISTERED AT CLINICALTRIALS.GOV: NCT01981954 and NCT01565694.

Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin.

To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6-7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0-24h,ss with and without darexaban-MR co-administration were within 0.80-1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0-24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94-1.12) and 1.11 (90 % CI: 1.05-1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80-1.25, indicating a lack of drug-drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.

Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects.

BACKGROUND: Darexaban (YM150) is a potent direct factor Xa (FXa) inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM-222714), which is a pharmacologically active metabolite. The objective of the present study was to evaluate the clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ascending multiple oral doses of darexaban in healthy non-elderly Caucasian and Japanese subjects. METHODS: A randomized, double-blind, placebo-controlled, single and multiple dose-escalating study of healthy Caucasian and Japanese male and female subjects was performed. The tested doses were 20, 60, 120 and 240 mg of darexaban. RESULTS: Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses in both Caucasians and Japanese. Cmax was about 17%-19% lower in Caucasians than in Japanese, although AUC appeared to be similar. The time-profiles of prothrombin time reported as the international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and FXa activity closely followed the time-concentration profile of darexaban glucuronide, and no clear differences were observed in ethnicity. Overall, 38 of the 82 enrolled subjects reported a total of 57 treatment-emergent adverse events (TEAEs). Fifty-five TEAEs were of mild intensity and two were of moderate intensity. CONCLUSION: It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability.

Absorption, metabolism and excretion of darexaban (YM150), a new direct factor Xa inhibitor in humans.

1. The absorption, metabolism and excretion of darexaban (YM150), a novel oral direct factor Xa inhibitor, were investigated after a single oral administration of [(14)C]darexaban maleate at a dose of 60 mg in healthy male human subjects. 2. [(14)C]Darexaban was rapidly absorbed, with both blood and plasma concentrations peaking at approximately 0.75 h post-dose. Plasma concentrations of darexaban glucuronide (M1), the pharmacological activity of which is equipotent to darexaban in vitro, also peaked at approximately 0.75 h. 3. Similar amounts of dosed radioactivity were excreted via faeces (51.9%) and urine (46.4%) by 168 h post-dose, suggesting that at least approximately half of the administered dose is absorbed from the gastrointestinal tract. 4. M1 was the major drug-related component in plasma and urine, accounting for up to 95.8% of radioactivity in plasma. The N-oxides of M1, a mixture of two diastereomers designated as M2 and M3, were also present in plasma and urine, accounting for up to 13.2% of radioactivity in plasma. In faeces, darexaban was the major drug-related component, and N-demethyl darexaban (M5) was detected as a minor metabolite. 5. These findings suggested that, following oral administration of darexaban in humans, M1 is quickly formed during first-pass metabolism via UDP-glucuronosyltransferases, exerting its pharmacological activity in blood before being excreted into urine and faeces.

The impact of hospital discharge on inappropriate hospital stay.

Appropriate hospital stay should be effective, efficient and tailored to patient needs. Previous studies have found that on average 20 per cent of hospital stay is inappropriate. Within obstetrics, inappropriate hospital stay consists mostly of delays in hospital discharge. The specific goals of this study were to reduce inappropriate hospital stay by fine-tuning patient logistics, increasing efficiency and providing more comfortable surroundings. New policies using strict discharge criteria were implemented. Total inappropriate hospital stay decreased from 13.3 to 7.2 per cent. The delay in discharge procedures halved. P-charts showed a decrease in inappropriate hospital stay, indicating the current process to be stable. Concludes that a significant reduction in inappropriate hospital stay was found following the implementation of innovative hospital discharge policies, indicating greater efficiency and accessibility of hospital services.

Appropriate length of extended day care.

Extended day care (EDC) is a one-day admission spending one night in hospital. Many EDC patients do not need hospital care over night, so probably they could be transferred to a day surgery setting, resulting in decreased costs and increased efficiency. The objectives of the study were to assess the appropriate length of extended day care (ALED) and a possible transfer to day surgery. ALED was defined as the time between the start of the surgical procedure and the final moment appropriate hospital care was provided. About 80 per cent of the patients could possibly have been treated in day surgery. The other patients could not be transferred, because of a prolonged ALED. With the implementation of new policies on admission to and discharge from the hospital and the use of altered types of operation room scheduling or patient logistics the transfer of most EDC patients to day surgery would be possible.

"Best practice" in inflammatory bowel disease: an international survey and audit.

Background: An observational study was conducted at eight university and four district hospitals in eight countries collaborating in clinical and epidemiological research in inflammatory bowel disease (IBD) to compare European health care facilities and to define current "best practice" with regard to IBD. Methods: The approach used in this multi-national survey was unique. Existing quality norms, developed for total hospital care by a specialized organization, were restricted to IBD-specific care and adapted to the frame of reference of the study group. In each center, these norms were surveyed by means of questionnaires and professional audits in all participating centers. The collected data were reported to the center, compared to data from other hospitals, and used to benchmark. Group consensus was reached with regard to defining current "best practice". Results: The observations in each center involved patient-oriented processes, technical and patient safety, and quality of the medical standard. Several findings could be directly implemented to improve IBD care in another hospital (benchmarks). These included a confidential relationship between health care worker(s) and patients, and availability of patient data. Conclusions: The observed benchmarks, in combination with other subjectively chosen "positive" procedures, have been defined as current "best practice in IBD", representing practical guidelines towards better quality of care in IBD.

Predictors of inappropriate hospital stay: a clinical case study.

OBJECTIVE: To assess the reasons for inappropriate patient stay (IPS) and to identify possible predictors of this inappropriate stay. DESIGN: The reasons for IPS were analyzed in a cross-sectional survey at two surgical one gynecologic and one obstetric ward, using a sample of 610 days of hospital stay by means of the Dutch Appropriateness Evaluation Protocol. SETTING: The study was conducted at the University Hospital Maastricht, a 715-bed hospital with a regional and teaching function, located in the southern part of The Netherlands. RESULTS: Results indicate that > 20% of the hospital stay was inappropriate. The reasons for IPS were statistically significantly related to the patients' age, the availability of home care and medical specialty. In a predictive model, only the specialty proved to be a predictor of IPS. Most of the IPS occurred during the first days of hospital stay and the days before the patient's discharge. CONCLUSION: A substantial proportion of hospital stay was found to be inappropriate, due to hospital procedures and the inability to refer patients to other care facilities or care providers. Analysis of the causes of IPS provided useful data for improvement actions. Efficient use of hospital resources should be promoted by reducing the delay in interventions and discharge procedures.

To stay or not to stay. The assessment of appropriate hospital stay: a Dutch report.

OBJECTIVE: To adjust the adult-medical Appropriateness Evaluation Protocol (AEP) into a valid and reliable instrument for use in the Dutch health care system, to assess the appropriateness of hospital stay and to identify the causes of inappropriateness. DESIGN: The appropriateness of hospital stay was assessed in a cross-sectional survey on a sample of over 4500 days of stay using a modified, Dutch version of the Appropriateness Evaluation Protocol (D-AEP). SETTING: The appropriateness of stay was assessed in five internal and surgical departments for adult acute care in the University Hospital of Maastricht, a 700-bed hospital with a teaching and regional function, located in the southern part of the Netherlands. RESULTS: The results showed that over 20% of the hospital stay was inappropriate. Half of the inappropriate hospital stay (45.1%) was due to (internal) hospital procedures. The D-AEP proved to be valid (kappa = 0.76; 95% confidence interval (95% CI) 0.68-0.84), reliable (kappa = 0.84; 95% CI 0.75-0.93) and easy to use. CONCLUSION: A substantial proportion of hospital stay was found to be inappropriate, due to hospital procedures and the inability to refer patients to other care facilities or care providers. The D-AEP can be used for monitoring the appropriate hospital stay and in detecting possible causes of inappropriate stay. Analysis of the causes of inappropriate hospital stay provided useful data for improvement actions.