Single-dose pharmacokinetics of the renin inhibitor ACT-077825 in elderly and young subjects of both sexes.

BACKGROUND/AIMS: The study objective was to investigate and compare the pharmacokinetics of a single oral dose of ACT-077825, a novel direct renin inhibitor, in young and elderly, male and female healthy subjects and to evaluate the safety and tolerability of ACT-077825 in these population groups. METHODS: A total of 32 healthy subjects were included in this single-center, open-label study. The subjects were divided into 4 groups, including 8 young male, 8 young female, 8 elderly male and 8 elderly female subjects. Each participant received a single 200-mg dose of ACT-077825. Blood samples were taken over 5 days (120 h) to determine the plasma levels of ACT-077825. Safety and tolerability were monitored using standard assessments before drug administration, on the administration day and at the end of the blood sampling period. RESULTS: Upon pooling male and female subjects, exposure was higher in elderly compared to young subjects, showing an increase of 65% for AUC0-∞, 40% for Cmax and 38% for t1/2. While young male and female subjects showed similar plasma profiles and exposure, a significant increase in exposure occurred with age in both sexes compared to younger subjects. The difference was largest between young and elderly females. Furthermore, the exposure to ACT-077825 was around 30% higher in elderly female compared to elderly male subjects. ACT-077825 was well tolerated by all groups, including the elderly females who showed the highest exposure. CONCLUSIONS: ACT-077825 exposure is moderately increased in elderly subjects. The clinical relevance of this observation should be explored in the context of further studies.

Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects.

Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence and fatigue were frequently reported. Other adverse events included headache and nausea. Muscular weakness was reported at a higher incidence only with the highest almorexant dose. The pharmacokinetic profile of almorexant was characterized by a median time to the maximum concentration of 1.5 hours, quick disposition with a distribution half-life of 1.6 hours, and rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours. Objective pharmacodynamic measures showed decreases in saccadic peak velocity and adaptive tracking performance and increases in body sway with the 400-mg dose of almorexant. Subjective assessments revealed a dose-dependent decrease in alertness. Almorexant had no effects on mood, calmness, subjective internal and external perception, and feeling high. These findings provide a solid basis to study the effects of almorexant in elderly patients with insomnia.

Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study.

Objective: Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Methods: Patients aged ≥65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results: 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions: Two-night oral administration of almorexant was effective and well tolerated in treating primary insomnia in elderly patients.

Adverse drug events caused by medication errors in medical inpatients.

PRINCIPLES: In view of growing concern in recent years regarding medication errors as causes of adverse drug events (ADEs), we explore the frequency and characteristics of error-associated ADEs in medical inpatients. METHODS: All patients with ADEs or ADErelated hospital admission in a cohort of medical inpatients identified by "event monitoring" (SAS/CHDM database, Br J Clin Pharmacol 2000:49:158-67) were evaluated independently by two experienced physicians. ADEs were first divided into ADEs occurring during cohort stay (incident ADE) and ADE present prior to/at admission. ADEs were then grouped as error-associated ADEs (eADEs: indication error, missed contraindication, wrong dosage regimen or inadequate surveillance) and adverse drug reactions (ADRs: indication established, no contraindications, appropriate dosage regimen and adequate surveillance). RESULTS: Among the 6383 patients analysed (100%), 481 (7.5%) experienced at least one incident ADE. Incident ADRs occurred in 457 (7.2%). Incident eADEs were recorded in 28 patients, corresponding to an eADE incidence of 0.4% (95% CI: 0.2, 0.7). Error types were missing/inappropriate indication (4 cases), missed contraindications (9), relative overdoses (8), absolute overdoses (3) and inadequate clinical surveillance (4). The responsible drugs included antithrombotics (6), cardiovascular drugs (5), antibiotics (5), hypnotics (4) and non-steroidal anti-inflammatory drugs (3). ADE-related hospital admissions were observed in 262 patients (4.1%); 183 (2.9%) were classified as ADRs and 79 (1.2%) as eADEs. CONCLUSIONS: Incident eADEs were observed in 1 out of 250 patients and accounted for approximately 6% of ADEs. In contrast, eADEs accounted for 30% of ADE-related hospital admissions. Hence, in medical inpatients, eADEs represented a small fraction of total incident ADEs, whereas they contributed significantly to hospital admissions.

Incidence of drug-induced liver injury in medical inpatients.

OBJECTIVES: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse. METHODS: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury. Thus, only cases with probable or certain causality according to the World Health Organization criteria were included. RESULTS: Among a total of 6383 patients, liver parameters were determined in 4610, and 489 among them fulfilled the CIOMS laboratory criteria. However, 401 patients had to be excluded because of disease-related liver injury and, thus, the study cohort consisted of 4209 patients at risk for DILI. Among a total of 88 DILI cases, 31 had no documented normal baseline liver parameters and, thus, represented prevalent cases. The remaining 57 represented incident DILI cases. Thus, the incidence of DILI was 1.4% (95% CI 1.0, 1.7). The drug classes most frequently causing DILI were heparins, antibacterials, tuberculostatics and antineoplastic agents. Among those, antineoplastic agents and tuberculostatics showed the highest incidence. Liver injury was not mentioned among the diagnoses or in the physician's discharge letter in about 52-68% of all cases. CONCLUSION: Approximately 1 in 100 patients develops DILI during hospitalisation in a department of medicine. Incidences of DILI were highest for antineoplastic agents and tuberculostatics. DILI is frequently missed and, therefore, DILI detection by diagnoses will result in misleadingly low incidence rates.