TITLE

Ziprasidone and the Corrected QT Interval

AUTHOR(S)
Camm, A. John; Karayal, Onur N.; Meltzer, Herbert; Kolluri, Sheela; O'Gorman, Cedric; Miceli, Jeffrey; Tensfeldt, Thomas; Kane, John M.
PUB. DATE
April 2012
SOURCE
CNS Drugs;2012, Vol. 26 Issue 4, p351
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5-19.5 milliseconds Ems]) in QTc over the range of 40-160 mg/d with a small incremental increase (22.5 ms) at 320 mgld. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (Cmax) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCT5). Objective: The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports and post-marketing surveillance. Methods: The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II-IY adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18 154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007. Results: A total of 4306 adults received ziprasidone in placeboand activecomparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc ⩾480 ms; 33 (0.8%) had a QTc ⩾450 ms. QTc prolongation 30 ms was observed in 389 subjects (9.0%); 60 ms in 30 (0.7%); and 75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms. Data from TM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects. A scatterplot of QTc prolongation against baseline QTc showed QTc prolongation 60 ms exclusively in adult subjects with a baseline QTc ⩽400 ms. The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6ms for each 100 ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs. Conclusions: These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase IT-TV RCTs, safety reports and post-marketing surveillance. The results of the analyses of pooled data from phase II-TV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ⩾60 ms (<1.0%) and rare observation of QTc ⩾480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post-marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.
ACCESSION #
75372358

 

Related Articles

  • An Idea Whose Time Came. Henderson, Lisa // Applied Clinical Trials;Aug2011, Vol. 20 Issue 8, p14 

    The article discusses the growing importance of patient-facing clinical trials in clinical research. It notes that the use of trial, which was developed by doctor Steve Cummings, did not progress, despite not requiring investigating new drugs (IND), due to the discovery of electronic data...

  • Pharma: Clinic Roundup.  // BioWorld Today;12/6/2012, Vol. 23 Issue 236, p4 

    The article reports on Pfizer Incorporated's randomized Phase II trial which showed that PD-0332991, combined with letrozole, significantly extended progression-free survival (PFS) compared to letrozole alone.

  • A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State. Patkar, Ashwin; Gilmer, William; Chi-un Pae; V�hringer, Paul A.; Ziffra, Michael; Pirok, Edward; Mulligan, Molly; Filkowski, Megan M.; Whitham, Elizabeth A.; Holtzman, Niki S.; Thommi, Sairah B.; Logvinenko, Tanya; Loebel, Antony; Masand, Prakash; Nassir Ghaemi, S. // PLoS ONE;Apr2012, Vol. 7 Issue 4, p1 

    Objective: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). Methods: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo...

  • A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State. Patkar, Ashwin; Gilmer, William; Chi-un Pae; Vöhringer, Paul A.; Ziffra, Michael; Pirok, Edward; Mulligan, Molly; Filkowski, Megan M.; Whitham, Elizabeth A.; Holtzman, Niki S.; Thommi, Sairah B.; Logvinenko, Tanya; Loebel, Antony; Masand, Prakash; Nassir Ghaemi, S. // PLoS ONE;Apr2012, Vol. 7 Issue 4, p1 

    Objective: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). Methods: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo...

  • The first published randomised controlled trial of laser treatment for vaginal atrophy raises serious questions. Buttini, Melissa J.; Maher, Christopher // Medical Journal of Australia;11/5/2018, Vol. 209 Issue 9, p376 

    The article presents a randomised controlled trial (RCT) which investigates the effectiveness of laser therapy for genitourinary syndrome of menopause (GSM) or vaginal atrophy.

  • Symptomatic use of beclomethasone plus albuterol and regular use of beclomethasone did not differ for control of mild asthma.  // ACP Journal Club;Nov/Dec2007, Vol. 147 Issue 3, p64 

    The article offers information on a study, investigating whether the symptomatic use of beclomethasone and albuterol in combination, is as effective as regular use of the same dose of beclomethasone, for asthma patients. It describes the randomized controlled trials, setting, and the patient's...

  • Review: Meglitinide analogues reduce glucose levels in type 2 diabetes, but morbidity and mortality effects are unknown.  // ACP Journal Club;Nov/Dec2007, Vol. 147 Issue 3, p65 

    The article offers information on a study investigating the effectiveness of meglitinide analogues (MAs) for patients with type 2 diabetes mellitus (DM). It describes the procedure and randomized controlled trials (RCTs), that were conducted during the study. The study revealed that MAs reduce...

  • Lamotrigine was more effective than carbamazepine, gabapentin, and topiramate for treatment failure in partial epilepsy.  // ACP Journal Club;Nov/Dec2007, Vol. 147 Issue 3, p74 

    The article focuses on a clinical study comparing the efficacy of gabapentin (GPT), carbamazepine (CBZ), topiramate (TPM), oxcarbazepine (OXC), and lamotrigine (LTG), in the treatment of patients with partial-onset seizures. It discusses the procedure followed, follow-up period, selection...

  • An easy intervention to improve short-term adherence to medications in community-dwelling older outpatients. A pilot non-randomised controlled trial. Bilotta, Claudio; Lucini, Anna; Nicolini, Paola; Vergani, Carlo // BMC Health Services Research;2011, Vol. 11 Issue 1, p158 

    Background: Complex interventions to improve compliance to pharmacological treatment in older people have given mixed results and are not easily applicable in clinical practice. The aim of this study was to test the short-term efficacy on self-reported medication adherence of an easy...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics