Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Almorexant, an Orexin Receptor Antagonist, in Healthy Elderly Subjects
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Abstract:
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.Keywords:
Orexin receptor
Pharmacodynamics
Crossover study
Tolerability
Fourteen cases of depression resistant to multiple treatments were treated by lithium augmentation of fluoxetine. Tolerability of the treatment was poor. Lithium and fluoxetine may be a possible treatment for resistant depression but there is caution regarding tolerability and toxicity with the relatively high doses of lithium used in this series.
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Onabotulinumtoxin A (onabotA) has shown efficacy in chronic migraine (CM), with good tolerability and a low rate of adverse effects, most of them not severe. The aim of this study is to evaluate tolerability and adverse effects of onabotA in clinical practice and to analyze if there is a relationship between tolerability to treatment administration, adverse effects' (AEs) occurrence and clinical response. We included patients with CM that received treatment with onabotA for the first time. Tolerability to treatment was evaluated by a 0-10 numeric rating scale (0: worst possible, 10: optimal tolerability). We assessed the presence of AEs by using a standardized questionnaire. Treatment response was based on the 50 and 75% responder rate between weeks 20 and 24, compared with the baseline, according to headache diaries. We analyzed whether the tolerability was associated with a higher frequency of AEs or a higher probability of clinical response. We included 105 patients, 87.7% female, with an age of 43.9 ± 10.7 years. Mean tolerability was 7.8/10 and 7.2/10 in the first and second onabotA administration, respectively. AEs were reported by (first-second) 71.4-68.6% patients. The percentage of patients with a 50% response was 56.3%. There was no association between tolerability and AEs' occurrence or clinical response.
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A single-center, crossover, randomized, double-blind, and controlled clinical study was conducted to assess the tolerability profile, especially with regard to gastrointestinal complaints, of oral supplementation with AB-Fortis®, a microencapsulated ferric saccharate (MFS), as compared with conventional ferrous sulphate (FS) in healthy premenopausal women. A dose of 60 mg/day of elemental iron was used. The test products were administered for 14 consecutive days with a washout period of two menstrual episodes and a minimum of one month between the two intervention periods. The subjects completed simple-to-answer questionnaires daily for 14 days during both the intervention and the washout periods, capturing the symptoms associated with oral iron supplementation and overall health aspects. Following product consumption, the incidences of symptoms, numbers of complaints/symptoms, overall intensity, and total days with symptoms were found to be significantly higher for FS consumption as compared to MFS. The better tolerability profile of MFS over FS was further substantiated when both products were compared to a real-life setting (i.e., the washout period). Overall, the administration of both study products was safe with no serious or significant adverse events reported. In summary, the current study shows the better tolerability of the MFS preparation when compared to that of the FS, presenting MFS as a well-tolerated and safe option for improving iron nutrition.
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Crossover study
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The paper considers the tolerability of Voltaren versus other nonsteroidal anti-inflammatory drugs, including generics. A wealth of clinical experience in using Voltaren leads to the conclusion on its good tolerability and significant anti-inflammatory and analgesic activities.
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Clinical Practice
Anti-inflammatory
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Skin lesions, increased transepidermal water loss, changes in pH in patients with allergodermathosis lead to a decrease in the protective mechanisms of the skin that makes individuals more susceptible to infections. The development of complications predefined the interest in improving topical therapy. The article presents a brief review of the literature data on high therapeutic activity and good tolerability of the topical drug Triderm. When compared with the original drug, the generics revealed differences in the structural and mechanical properties, which affects bioavailability. A comparison of therapeutic efficacy and tolerability has shown that Triderm is more effective, and comparable to Akriderm GK in terms of tolerability.
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Transepidermal water loss
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Summary: Purpose: To evaluate the tolerability and safety of gabapentin (GBP) as add‐on therapy for seizure control. Methods: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages ≤1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP ≤1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow‐up contact. Results: A total of 2,216 patients enrolled in this open‐label, 16‐week study and were evaluable for safety. Of these, 74.0% completed the 16‐week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only ≤1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at ≤1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. Conclusions: Gabapentin doses >1,800 mg/day were as well tolerated as doses ≤1,800 mg/day and were not associated with more adverse events.
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Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability.The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability".Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability.Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare.
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Pharmacodynamics
ED50
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Objective:This study was designed to characterize the pharmacokinetics and pharmacodynamics of high dose epirubicin in cancer patients Methods:Eleven cancer patients were administered a dose of 100 mg/m 2 epirubicin The concentration of epirubicin in the blood were determined by high performance liquid chromatographic (HPLC)assay The modelling data were performed with a compartment pharmacokinetic modelling program (PCNONLIN) Hematological toxicity was used as the pharmacodynamic index The relationships between the pharmacokinetics and pharmacodynamics and other factors affecting dose modulation were assessed Results: The pharmacokinetics of high dose epirubicin was best described by a typical three compartment model It showed wide interindividual variation There was no correlation between its pharmacokinetics and pharmacodynamics Age was negatively correlated with epirubicin clearance Conclusions: There was no difference for the pharmacokinetic parameters between high dose and low dose Total clearance appears to be decreased with age and indicating that it is necessiary to reduce dose for the elderly patients Tolerance of the patients receiving a dose of 100 mg/m 2 epirubicin was good
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Thirty to 40% of patients using topical treatments do not comply with their treatment regimen.To examine how tolerability is assessed, tolerability ratings, and clinical significance of tolerability ratings of topical antimicrobials for acne.A literature search was performed using the terms "tolerability AND acne AND (benzoyl peroxide OR antimicrobial OR clindamycin OR erythromycin OR dapsone OR sulfur OR sulfacetamide)." Inclusion criteria were: 1) evaluation of tolerability, 2) use of an identified topical antimicrobial for acne treatment without combination retinoid use, 3) an original study, in English.Thirty-four of 132 articles met the inclusion criteria. Tolerability was measured through subject and investigator assessment of specific tolerability parameters and by reporting of adverse events. Nearly all of the acne treatments were well tolerated. Treatment related study discontinuation rates were low and had little to no relation to the degree of tolerability measures.Patients may be more adherent in clinical trials than in clinical practice. Differences in the measure used to assess tolerability make comparisons difficult.Topical antimicrobial acne therapy is generally well tolerated. Discontinuation rates are low under study conditions. Tolerability of topical antimicrobial therapy for acne may not have great clinical significance.
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Discontinuation
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