Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers

Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5-, 10-, or 20-mg IM doses of ziprasidone in 24 subjects and an open-label 3-way crossover trial of 5-mg intravenous (IV), 5-mg IM, and 20-mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose-related increases in exposure observed. The mean IM elimination t(1/2) was short and approximately 2.5 hours. The mean bioavailability for the 5-mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia.     

Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia

This randomized, parallel-group, open study investigated the efficacy and safety of risperidone oral solution (RIS-OS) in combination with clonazepam and intramuscular haloperidol for the treatment of acute agitation in patients with schizophrenia, and the study explored the possibility of decreasing the efficacy of an acute 6-week treatment by switching intramuscular haloperidol injection to RIS-OS. Two hundred and five agitation-exhibiting schizophrenic inpatients at six hospitals were originally included in the study. The 47-day trial consisted of 5 days (session I) of receiving either oral treatment (RIS-OS plus clonazepam) or intramuscular treatment (intramuscular haloperidol) and a 42-day (session II) period of either withdrawing from clonazepam or shifting from intramuscular haloperidol to a RIS-OS period. The primary efficacy outcome was measured as the change in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) in session I and the change in the PANSS in session II. Safety was assessed by the frequency of the adverse events. Mean PANSS-EC improvement was significant after 5 days of treatment in both groups (P>0.05) and was similar between the two treatment groups (P<0.01). Most patients' PANSS-EC scores improved or remained stable during the drawback/shift treatment period. Efficacy was not significantly different between the two treatment groups after the 6-week treatment (P>0.05). However, combination treatment exhibited greater efficacy, and adverse events, especially extrapyramidal symptoms, were lower with the oral treatment than with the intramuscular treatment in session I. These results show that RIS-OS in combination with clonazepam is an effective treatment, comparable with intramuscular haloperidol, and is well-tolerated for acute agitation in patients with schizophrenia.     

齐拉西酮注射液治疗精神分裂症激越症状的研究

目的本研究应用氟哌啶醇注射液作为对照,评价齐拉西酮注射液治疗精神分裂症激越患者的疗效、安全性和耐受性。方法连续入组急性精神分裂症患者,按照1：1的比例随机分配到齐拉西酮注射液治疗组（试验组）和氟哌啶醇注射液治疗组（对照组）,对患者进行筛选访视、基线访视,以及肌注治疗第一剂药后的2、4、24、48h和72h的访视。采用简明精神评定量表（BPRS）评价主要疗效,Simpson-Angus量表评定药物的锥体外系反应。结果两组均纳入受试者30例。药物治疗72h后与基线比较,试验组BPRS总分减分平均为12.55±6.88,对照组BPRS总分减分平均为15.60±5.94。两组主要疗效指标差异无统计学意义（P=0.110）。试验组未见锥体外系不良反应,Simpson-Angus量表评分在治疗前后差异无统计学意义（P=0.16）;对照组出现锥体外系不良反应,治疗前后差异有统计学意义（P=0.02）。结论甲磺酸齐拉西酮注射液能够快速有效控制精神分裂症急性激越症状,疗效与氟哌啶醇注射液相当,不良反应轻微,安全性、耐受性好,值得临床推广应用。     

The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients

In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

齐拉西酮与氟哌啶醇治疗精神分裂症对照研究

目的：探讨齐拉西酮治疗精神分裂症的疗效及不良反应。方法：将符合入组标准的100例精神分裂症患者随机分为齐拉西酮组与氟哌啶醇组各50例。进行为期8周的治疗。采用阳性与阴性症状量表（PANSS）评定疗效、副反应量表CRESS）评定副反应。结果：氟哌啶醇组有效率为74％,显效率为38％;齐拉西酮组有效率为84％,显效率为72％。两组药物显效率比较,差异有统计学意义（P〈0．01）;阳性与阴性症状量表评分,两组治疗第4周末起总分及各因子分与治疗前比较,差异有统计学意义（P均〈0．01）。结论：该两种药物对精神分裂症均有确切疗效,且安全性相对较高,齐拉西酮对症状的改善效果更好,不良反应轻微。     

Pharmacokinetics and therapeutics of acute intramuscular ziprasidone

Patients with acute psychosis often exhibit agitation, which can be distressing and hazardous to others as well as to the patient. In such psychiatric emergencies, intramuscular antipsychotic agents can be easier to administer than oral formulations, and they have the added advantage of more rapid absorption and a faster onset of action. However, intramuscular formulations of conventional antipsychotics, which have been the standard treatment, are associated with acute dystonia and other movement disorder-related adverse events. Ziprasidone is the first atypical antipsychotic to be clinically available in both intramuscular and oral formulations in the US. The intramuscular formulation of ziprasidone, ziprasidone mesylate, uses sulfobutylether beta-cyclodextrin to solubilise the drug by complexation. The pharmacokinetics of intramuscular ziprasidone include rapid attainment of therapeutic drug level (time to reach peak serum concentration [tmax]相似文献   

齐拉西酮与氟哌啶醇治疗精神分裂症激越症状的效果及安全性比较

目的探讨齐拉西酮与氟哌啶醇治疗精神分裂症激越症状的效果及安全性比较。方法选取医院2017年1月～2018年12月收治80例精神分裂症伴激越症状患者,随机分为观察组和对照组各40例,对照组给予氟哌啶醇,观察组给予齐拉西酮。治疗前后,评估两组患者阳性与阴性症状评分(PANSS)、阳性与阴性症状兴奋因子(PANSS-EC)、认知功能评分(WMS、TMT),并记录两组患者不良反应事件。结果治疗后,两组PANSS与PANSS-EC评分均优于治疗前(P 0.05),但两组间比较差异无统计学意义(P 0.05);治疗后,观察组患者WMS、TMT评分情况均优于对照组(P 0.05);治疗后,两组患者不良反应发生率差异无统计学意义(P 0.05),但观察组稍好于对照组。结论应用齐拉西酮与氟哌啶醇治疗精神分裂激越症患者,其激越症状治疗及两种药物安全性方面相当,但齐拉西酮在治疗认知功能方面疗效更好,在引起锥体外系不良反应方面效果更安全,更具优势。     

Intramuscular aripiprazole or haloperidol and transition to oral therapy in patients with agitation associated with schizophrenia: sub-analysis of a double-blind study

ABSTRACT

Objective: A sub-population analysis of 325 patients with agitation (Positive and Negative Syndrome Scale Excited Component [PEC] score ≥ 15 and ≤ 32; score of ≥ 4 on ≥ 2 items) associated with schizophrenia in a randomized, double-blind study investigating the efficacy and tolerability of intramuscular (IM) aripiprazole 9.75?mg, IM haloperidol 6.5?mg, or IM placebo and the transition to oral therapy.

Research design and methods: Over 24?h, patients could receive up to three IM injections; the second and third administered ≥ 2 and ≥ 4?h, respectively, after the first, if deemed clinically necessary. Following IM treatment, oral aripiprazole or haloperidol was administered for 4 days. The primary efficacy measure was the mean change in PEC score from baseline at 2?h.

Results: At 2?h, mean improvements in PEC scores with IM aripiprazole (–8.0) were significantly greater versus IM placebo (–5.7; p ≤ 0.01), and similar versus IM haloperidol (–8.3). Secondary efficacy measures also significantly improved with active IM treatment versus IM placebo. Continuation with oral treatment provided continued efficacy with both active treatments. The safety profiles of IM and oral aripiprazole were similar. The incidence of extrapyramidal symptom-related adverse events was 0% with IM aripiprazole, 1.6% with IM placebo and 16.5% with IM haloperidol.

Conclusion: Intramuscular aripiprazole is effective in patients with acute agitation associated with schizophrenia, comparable to IM haloperidol, and enables convenient transfer to oral aripiprazole therapy.     

Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia

This multicentre, parallel-group study compared the efficacy and tolerability of ziprasidone and chlorpromazine in treatment-resistant schizophrenia (at least three treatment periods of at least 6 weeks each with two or more antipsychotic agents during the past 5 years without significant response) that was unresponsive to 6 weeks of open-label haloperidol (相似文献   

齐哌西酮与氟哌啶醇治疗精神分裂症的疗效和安全性比较

目的：验证齐哌西酮治疗精神分裂症的疗效及安全性。方法：采用随机、双盲、双模拟、平行对照研究。治疗d 1～4,试验组每日早餐后服齐哌西酮20 mg及氟哌啶醇安慰剂1片,对照组每日早餐后服氟哌啶醇2 mg及齐哌西酮安慰剂1片；治疗d 5～42,试验组每日早、晚餐后服齐哌西酮20 mg及氟哌啶醇安慰剂1片,对照组每日早、晚餐后服氟哌啶醇2 mg及齐哌西酮安慰剂1片。疗程6 wk。结果：完成6 wk治疗的精神分裂症病人共57例,其中试验组(齐哌西酮组)29例,对照组(氟哌啶醇组)28例。治疗结束时,2组PANSS和BPRS评分较入组时均显著减低(P＜0.05)；PANSS总减分率：齐哌西酮组为(66±s 28)%,氟哌啶醇组为(66±26)%；临床总有效率：齐哌西酮组66%,氟哌啶醇组71%,2组疗效差异无显著意义(P＞0.05)。2组的不良反应发生率差异无显著意义,齐哌西酮组失眠的发生率显著高于氟哌啶醇组(P＜0.05)。结论：国产齐哌西酮治疗精神分裂症有明显疗效,未见明显不良反应。     

The effect of food on the absorption of oral ziprasidone

Oral ziprasidone bioavailability is increased when taken with food. Here we describe two pharmacokinetic studies to quantify the impact of food on ziprasidone absorption in healthy volunteers. The first, an open-label, six-way crossover study, investigated ziprasidone absorption in eight healthy men. Subjects received oral ziprasidone (20, 40, and 80 mg) after an 8-hour fast or immediately following a US Food and Drug Administration standard meal (50% fat). In this study, area under the serum concentration- time curve (AUC) was greater in fed than in fasting states at each dose (20 mg, +48%; 40 mg, +87%; 80 mg, +101%). Under fasting conditions, increases in AUC and maximum drug concentration (Cmax) were less than dose-proportional; under fed conditions, they were dose-proportional. The second, an open-label, randomized, three-way crossover study, explored the impact of dietary fat on ziprasidone absorption in 14 healthy subjects. Subjects received ziprasidone (40 mg) under three conditions: fasting, with a high-fat meal (60% fat), and with a moderate-fat (30% fat) meal. AUC and Cmax under fed conditions increased by 104% and 84% (60%-fat meal) and 79% and 98% (30%-fat meal) , respectively, relative to the fasting state. There was no clear difference in ziprasidone bioavailability between the fed groups, suggesting that meal fat content is not a major determinant of bioavailability. Less pharmacokinetic variability was observed in the fed state, suggesting more consistent absorption of ziprasidone. These results demonstrate that administration of ziprasidone with food is crucial to ensure optimal, reliable dose-dependent bioavailability and thus predictable symptom control and tolerability.     

盐酸齐拉西酮和氟哌啶醇对精神分裂症认知灵活性的疗效比较

目的:探讨比较盐酸齐拉西酮和氟哌啶醇对精神分裂症患者认知灵活性的疗效.方法:对50例服用齐拉西酮维持治疗与50例服用氟哌啶醇维持治疗的精神分裂症患者进行12个月随访,采用威斯康星卡片分类(WCST)和连线测验(Trailing Making)评估患者的认知灵活性.结果:维持治疗12个月末齐拉西酮组和氟哌啶醇组的WCST测验中的总分类次数、错误数、持续错误数、非持续错误数以及连线测验各指标(连线A、B时间,A、B错误数和A、B犯规数)均显著下降(P＜0.05),并且齐拉西酮组的持续错误数减分率显著高于氟哌啶醇组(P＜0.05).治疗后,两组连线测验成绩减分率差异无统计学意义(P＞0.05).结论:齐拉西酮较氟哌啶醇更有益于改善精神分裂症患者的认知灵活性.     

A pilot study of intramuscular ziprasidone in the short-term treatment of patients with acute exacerbation of schizophrenia

Ziprasidone is a novel antipsychotic which, in oral formulation, has been shown to be effective and well tolerated in the treatment of acute psychosis. This pilot study examined the efficacy and tolerability of the intramuscular (IM) formulation and the transition from IM to oral ziprasidone in patients with acute schizophrenia. The study design was an open, prospective, 5-day treatment trial of IM ziprasidone followed by oral dosing in 12 patients with acute exacerbation of schizophrenia. Various doses (2.5, 5, 10, or 20 mg) up to 60 mg/day total were administered over 3 days, followed by transition to oral ziprasidone on Days 4-5. All patients completed the study. Mean improvements between baseline and Day 3 were observed in Brief Psychiatric Rating Scale (47.8 to 28.9) and Clinical Global Impression of Severity (6.1 to 5.3), and improvements were maintained on Days 4 and 5. No extrapyramidal syndrome, acute dystonia, or serious adverse events were reported. In these patients, IM ziprasidone 20-60 mg/day reduced psychomotor agitation and other symptoms of psychosis. The transition from IM to oral ziprasidone was well tolerated. Copyright 2000 John Wiley & Sons, Ltd.     

The gastrointestinal tolerability and safety of oral bisphosphonates

Oral bisphosphonates are effective for osteoporosis and other hyperresorptive bone disorders. Although well-tolerated in efficacy trials, some oral aminobisphosphonates have been associated with upper gastrointestinal intolerance and injury in postmarketing experience. Clinical trials often underestimate the rate of adverse events in clinical practice, and ethics prohibit direct evaluation of toxicity in high-risk patients. Accordingly, animal models and endoscopy studies of oral bisphosphonates provide valuable insight. It is unclear whether variation in ulcerogenic potential reflects differences in dosing, formulation or chemical structure. Furthermore, the clinical relevance of endoscopic lesions is uncertain. Ongoing postmarketing review will determine whether differences in endoscopic damage predict tolerability and safety in clinical practice. However, physicians and patients should consider risk factors for oesophageal injury when initiating therapy.     

Pharmacokinetics and tolerability of intramuscular, oral and intravenous aripiprazole in healthy subjects and in patients with schizophrenia

BACKGROUND AND OBJECTIVE: Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. SUBJECTS AND METHODS: Study 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the bioavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). MAIN OUTCOME MEASURES: The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. RESULTS: In study 1, the geometric mean values for the absolute bioavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the C(max) values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. CONCLUSION: More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.     

The gastrointestinal tolerability and safety of oral bisphosphonates

Oral bisphosphonates are effective for osteoporosis and other hyperresorptive bone disorders. Although well-tolerated in efficacy trials, some oral aminobisphosphonates have been associated with upper gastrointestinal intolerance and injury in postmarketing experience. Clinical trials often underestimate the rate of adverse events in clinical practice, and ethics prohibit direct evaluation of toxicity in high-risk patients. Accordingly, animal models and endoscopy studies of oral bisphosphonates provide valuable insight. It is unclear whether variation in ulcerogenic potential reflects differences in dosing, formulation or chemical structure. Furthermore, the clinical relevance of endoscopic lesions is uncertain. Ongoing postmarketing review will determine whether differences in endoscopic damage predict tolerability and safety in clinical practice. However, physicians and patients should consider risk factors for oesophageal injury when initiating therapy.     

A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tolerability of oral ziprasidone in patients with schizophrenia.

This multicenter, uncontrolled, naturalistic study evaluated the effectiveness and tolerability of 6 months of treatment with ziprasidone in 1266 patients with a diagnosis of schizophrenia. The percentage of responders (at least 30% reduction in PANSS total score) in the primary analysis sample (n=1022) was 47.3% (95% CI 44.2-50.4) at the end of the study. Patients showed a significant and clinically relevant reduction in the PANSS total, positive, negative and general psychopathology subscales scores (effect size of 1.60, 1.83, 0.62 and 1.40 respectively). Overall, 453 (35.8%) patients withdrew from the study; 9.3% withdrew owing to adverse events. Ziprasidone doses greater than 120 mg/day were associated with a lower risk of discontinuation for any cause (OR 0.46, 95% CI 0.33-0.65) Ziprasidone was well tolerated. Most common side effects were: insomnia, somnolence and nervousness. The effectiveness and tolerability of ziprasidone in clinical practice are consistent to those previously shown in the more restricted and homogeneous populations of clinical trials.