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Citrome L.,New York Medical College | Baker R.,Otsuka Pharmaceutical Development and Commercialization Inc
Journal of Clinical Psychiatry | Year: 2013

Objective: To examine the risk of cardiovascular outcomes and diabetes mellitus in patients prescribed second-generation antipsychotics. Method: From the MarketScan claims database, nondiabetic adults prescribed aripiprazole between July 2003 and March 2010 were propensity core- matched with patients prescribed olanzapine, quetiapine, risperidone, and ziprasidone. Patients were followed through the claims for International Classification of Diseases, Ninth Revision codes indicating myocardial infarction, stroke, heart failure, coronary bypass/angioplasty procedures, and incident diabetes. Incidence rates of each outcome were calculated and compared between aripiprazole and the other secondgeneration antipsychotics using Cox models. Results: Aripiprazole initiators were matched 1:1 to 9,917 olanzapine, 14,935 quetiapine, 10,192 risperidone, and 5,696 ziprasidone initiators. Increased risk was found with olanzapine for stroke (hazard ratio = 1.43; 95% confidence interval, 1.05-1.95) and any cardiovascular event (1.28; 1.05-1.55); with quetiapine for stroke (1.58; 1.19-2.09), heart failure (1.55; 1.15-2.11), and any cardiovascular event (1.50; 1.25-1.79); and with risperidone for stroke (1.54; 1.12-2.12), heart failure (1.43; 1.02-1.99), and any cardiovascular event (1.49; 1.21-1.83). Ziprasidone showed no significant difference in risk from aripiprazole for any outcome. Incidence of diabetes ranged from 18 to 21 events per 1,000 person-years in each cohort and did not differ significantly between second-generation drugs. Conclusions: This analysis of real-world data found lower risk of some cardiovascular events with aripiprazole than with olanzapine, quetiapine, or risperidone, but no differences were found with ziprasidone. There were no significant differences in risk of diabetes. Limitations include use of claims data and inability to adequately control for differential prescribing of second-generation antipsychotics to patients at higher risk of diabetes. © Copyright 2013 Physicians Postgraduate Press, Inc.

Meyers C.A.,University of Texas M. D. Anderson Cancer Center | Rock E.P.,Otsuka Pharmaceutical Development and Commercialization Inc | Fine H.A.,U.S. National Cancer Institute
Journal of Neuro-Oncology | Year: 2012

As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function. © Springer Science+Business Media, LLC. 2012.

Citrome L.,New York Medical College | Kalsekar I.,Bristol Myers Squibb | Baker R.A.,Otsuka Pharmaceutical Development and Commercialization Inc. | Hebden T.,Bristol Myers Squibb
Current Medical Research and Opinion | Year: 2014

Background: Metabolic abnormalities observed with atypical antipsychotic treatment may be specific to each antipsychotic medication. The association between atypical antipsychotics and risk factors for cardiovascular disease prompted the American Diabetes Association (ADA) and the American Psychiatric Association (APA) to issue a consensus statement that categorized aripiprazole and ziprasidone as atypical antipsychotics with a lower likelihood of metabolic abnormalities. Objective: The aim of the current systematic review was to evaluate real-world studies (i.e. observational/naturalistic and open-label studies) assessing the risk for weight gain, dyslipidemia, glucose abnormalities, and diabetes mellitus in adult patients receiving treatment with atypical antipsychotics, with a specific focus on aripiprazole. Methods: A systematic PubMed search for articles published between 1 January 2000 and 4 October 2011 was performed using the following search terms in the title and abstract: aripiprazole, atypical, glucose, insulin, cholesterol, triglycerides, diabetes, hemoglobin A1c, weight, body mass index, and hyperlipidemia. Results: Twenty-two peer-reviewed articles were found that assessed the metabolic effects associated with aripiprazole treatment, including studies from small observational trials to large databases (n=15 to n>1,700,000). Thirteen articles reported observational or naturalistic studies, and nine were open-label trials evaluating weight gain, dyslipidemia, glucose abnormalities, and the risk of developing diabetes in adult patients receiving treatment with aripiprazole. Compared with other atypical antipsychotics, aripiprazole was either less likely to have an impact or had a comparable impact on weight gain and dyslipidemia; the degree of effect appeared to be dependent on study design. In addition, there was less risk of diabetes mellitus with aripiprazole compared with most other atypical antipsychotic agents. Conclusions: Consistent with data from randomized controlled studies, the current review of observational/naturalistic and open-label studies suggests aripiprazole may be associated with a lower risk than other commonly used atypical antipsychotics for metabolic adverse events in adults, consistent with the ADA/APA consensus statement. © 2014 Informa UK Ltd.

Berl T.,University of Colorado at Denver | Quittnat-Pelletier F.,University of Toronto | Verbalis J.G.,Georgetown University | Schrier R.W.,University of Colorado at Denver | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2010

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (≤30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety. Copyright © 2010 by the American Society of Nephrology.

Kubota R.,Acucela Inc. | Boman N.L.,Acucela Inc. | David R.,Acucela Inc. | Mallikaarjun S.,Otsuka Pharmaceutical Development and Commercialization Inc | And 2 more authors.
Retina | Year: 2012

BACKGROUND: ACU-4429 is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex and, in mouse models of retinal degeneration, prevents the accumulation of A2E.The purpose of this study was to assess the tolerability, pharmacokinetics, pharmacodynamics, and safety of a single, orally administered dose of ACU-4429 in healthy subjects. METHODS: Sequential cohorts were administered single doses ranging from 2 mg to 75 mg. Full-field electroretinograms were recorded before and after exposure to full-field bleaching light. Pharmacokinetics samples were taken at predetermined times. Safety assessments included adverse events, vital signs, clinical laboratory assays, electrocardiograms, and ophthalmologic examination. RESULTS: After 45-minute dark adaptation, electroretinographic findings demonstrated a dose-related slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the concentration curve and peak plasma concentration increased proportionally with increasing doses. Median time to peak concentration was 4 hours postdose. Mean elimination mean half-life was 4 hours to 6 hours. Adverse events were mild and visual in nature (dyschromatopsia and alteration in dark adaptation), transient, and resolved within a few days. Adverse event frequency was dose dependent. CONCLUSION: Oral administration of ACU-4429 produced a dose-dependent inhibition of the b-wave of the electroretinograms, was well tolerated up to 75 mg, and demonstrated linear pharmacokinetics across doses. Copyright © 2011 Lippincott Williams &Wilkins.

Shoaf S.E.,Otsuka Pharmaceutical Development and Commercialization Inc. | Mallikaarjun S.,Otsuka Pharmaceutical Development and Commercialization Inc. | Bricmont P.,Otsuka Pharmaceutical Development and Commercialization Inc.
European Journal of Clinical Pharmacology | Year: 2012

Purpose: Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US and Europe) or extracellular volume expansion despite taking other diuretics (Japan). In vitro studies indicated that tolvaptan was a CYP3A4 substrate. Methods: A single-center, randomized, crossover trial of 60-mg tolvaptan with 240 mL of water or with 240 mL of reconstituted grapefruit juice (washout period of 72 h between doses) was conducted in 20 healthy subjects. Blood samples for tolvaptan plasma concentrations were obtained for 48 h postdose. Results: All subjects completed the trial. Following co-administration with grapefruit juice, tolvaptan concentrations were elevated compared with tolvaptan alone for only 16 h postdose; consequently, the mean elimination half-life of tolvaptan was unchanged, 5.7 vs 5.1 h respectively. The mean maximal plasma concentration (C max) and the area under the curve (AUC ∞) of tolvaptan were increased 1.86- and 1.56-fold respectively when co-administered with grapefruit juice. Conclusions: It appears that grapefruit juice increases the bioavailability of tolvaptan, but does not affect its systemic elimination. The adverse event profile was consistent with the aquaretic effect of tolvaptan as urinary frequency, thirst, and dry mouth were the most frequently reported events. © 2011 Springer-Verlag.

Shoaf S.E.,Otsuka Pharmaceutical Development and Commercialization Inc. | Bricmont P.,Otsuka Pharmaceutical Development and Commercialization Inc. | Mallikaarjun S.,Otsuka Pharmaceutical Development and Commercialization Inc.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was determined in a single-center, open-label, sequential administration trial in which intravenous (i.v.) placebo (Day -2), i.v. 1 mg tolvaptan (Day 1) and an oral 30 mg tablet (Day 8) were administered to 14 healthy subjects. Urine volume and osmolality were determined on Days -2, 1 and 8 at multiple intervals postdose; 24-h fluid balance was also assessed. On Days 1 and 8, blood samples for tolvaptan were collected for 48 h postdose. Mean absolute bioavailability was determined to be 56% (range 42 - 80). Mean peak tolvaptan concentration at 1 h (end-of-infusion) was 32.7 (range 18 - 45) ng/ml compared to 231 (range 87 -410) ng/ml for the oral dose. In the 4-h period from start of the 1 mg tolvaptan i.v. infusion, 12 of 14 subjects experienced increased urine volume and decreased urine osmolality; both parameters were affected for 24 h postdose following the 30 mg oral dose. Minimally effective concentrations are rapidly achieved after oral dosing as all subjects had tolvaptan concentrations > 20 ng/ml at 1 h postdose. ©2012 Dustri-Verlag Dr. K. Feistle.

Shoaf S.E.,Otsuka Pharmaceutical Development and Commercialization Inc | Ryul Kim S.,Otsuka Pharmaceutical Co. | Bricmont P.,Otsuka Pharmaceutical Development and Commercialization Inc | Mallikaarjun S.,Otsuka Pharmaceutical Development and Commercialization Inc
European Journal of Clinical Pharmacology | Year: 2012

Purpose To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions. Methods This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30 mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24 h postdose. Results In the fasted state, the plasma tolvaptan Cmax and AUC∞ geometric mean ratios (90 % confidence interval) were 1.105 (0.845-1.444) and 1.145 (0.843-1.554) for Japanese compared to Caucasian subjects. A HFM increased the Cmax and AUC∞ values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men. Conclusion Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food. © Springer-Verlag 2012.

Findling R.L.,Johns Hopkins Hospital | McQuade R.D.,Otsuka Pharmaceutical Development and Commercialization Inc
Journal of Clinical Psychiatry | Year: 2014

Objective: To evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients. Method: This multicenter, double-blind, randomized, placebocontrolled, relapse-prevention trial enrolled patients (6-17 years) who met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DMS-IV-TR) criteria for autistic disorder and who also had serious behavioral problems (ie, tantrums, aggression, self-injurious behavior, or a combination of these behavioral problems) between March 2011 and June 2012. In phase 1, single-blind aripiprazole was flexibly dosed (2-15 mg/d) for 13-26 weeks. Patients with a stable response (≥ 25% decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of "much improved" or "very much improved" on the Clinical Global Impressions-Improvement scale) for 12 consecutive weeks were randomized into phase 2 to continue aripiprazole or switch to placebo. Treatment was continued until relapse or up to 16 weeks. The primary end point was time from randomization to relapse. Results: Eighty-five patients were randomized in phase 2. The difference in time to relapse between aripiprazole and placebo was not statistically significant (P = .097). Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo (hazard ratio [HR] = 0.57; number needed to treat [NNT] = 6). The most common adverse events during phase 1 were weight increase (25.2%), somnolence (14.8%), and vomiting (14.2%); and, during phase 2 (aripiprazole vs placebo), they were upper respiratory tract infection (10.3% vs 2.3%), constipation (5.1% vs 0%), and movement disorder (5.1% vs 0%). Conclusions: In this study, there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy. However, the HR and NNT suggest some patients will benefit from maintenance treatment. Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment. © Copyright 2014 Physicians Postgraduate Press, Inc.

Shoaf S.E.,Otsuka Pharmaceutical Development and Commercialization Inc. | Bricmont P.,Otsuka Pharmaceutical Development and Commercialization Inc. | Mallikaarjun S.,Otsuka Pharmaceutical Development and Commercialization Inc.
British Journal of Clinical Pharmacology | Year: 2012

AIMS In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed. METHODS For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30mg dose of tolvaptan (n= 19) or matching placebo (n= 5) on day 1 with a 72h washout followed by a 3 day regimen of 200mg ketoconazole, once daily with 30mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240mg tolvaptan with 48h washout followed by a 7 day regimen of 600mg rifampicin, once daily, with 240mg tolvaptan also given on the seventh day. RESULTS When co-administered with ketoconazole, mean C max and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean C max and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8l. CONCLUSIONS Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

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