Iloperidone: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability, regulatory affairs, and an opinion.
ABSTRACT Iloperidone is a newly commercialized second-generation (atypical) antipsychotic approved for the acute treatment of schizophrenia in adults.
the purpose of this review is to describe the pharmacokinetic profile of iloperidone and its clinical implications in the treatment of schizophrenia. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety data, and regulatory affairs.
the reader will have an understanding of the pharmacokinetics and overall metabolism of iloperidone within the context of efficacy and safety.
time to peak plasma concentration occurs in 2 - 4 h but elimination half-life is 18 h for extensive CYP2D6 metabolizers and 33 h for poor CYP2D6 metabolizers, suggesting that once or twice daily dosing would be feasible. Dizziness and/or postural hypotension are the limiting factors for how fast iloperidone can be titrated, and is explained by iloperidone and its metabolites' norepinephrine alpha 1 antagonism. Efficacy of iloperidone appears similar to that for ziprasidone and haloperidol, but iloperidone may be inferior in efficacy to risperidone. Iloperidone can prolong the ECG QT interval. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose, little in the way of prolactin elevation, and an absence of extrapyramidal adverse effects, including akathisia.
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ABSTRACT: This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype. Among pharmacokinetic markers, CYP2D6 metabolizer phenotype has clear clinical significance, as it impacts dosing considerations for aripiprazole, iloperidone and risperidone, and variants of the ABCB1 gene hold promise as biomarkers for dosing for olanzapine and clozapine. Among pharmacodynamic variants, the TaqIA1 allele of the DRD2 gene, the DRD3 (Ser9Gly) polymorphism, and the HTR2C -759C/T polymorphism have emerged as potential biomarkers for response and/or side effects. However, large-scale candidate gene studies and genome-wide association studies indicate that pharmacotypic genes may ultimately prove to be the richest source of biomarkers for response and side effect profiles for second-generation antipsychotics.Pharmacogenomics 04/2014; 15(6):869-884. DOI:10.2217/pgs.14.50 · 3.43 Impact Factor
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ABSTRACT: The crystal engineering strategy was used to facilitate the supramolecular synthesis of a new crystalline phase of iloperidone, an atypical psychotropic drug with known problems related to poor dissolution and absorption profile. The novel crystal forms Jilin University China-Cocrystal-1 (JUC-C1), Jilin University China-Cocrystal-2 (JUC-C2), and Jilin University China-Cocrystal-3 (JUC-C3) of iloperidone with 3-hydroxybenzoic acid (3-HBA), 2,3-dihydroxybenzoic acid (2,3-DHBA), and 3,5-dihydroxybenzoic acid (3,5-DHBA) were obtained using the reaction crystallization method (RCM). The dissolution and pharmacokinetics studies were performed to exploit this atypical psychotropic drug. In the dissolution experiment, JUC-C1, JUC-C2, and JUC-C3 (JUC-C1–3) showed a much faster dissolution rate than the original active pharmaceutical ingredient (API) in simulated gastric fluid media (pH = 1.2). Furthermore, pharmacokinetic behavior of JUC-C1–3 and API was investigated to evaluate the effectiveness of this strategy for enhancing the oral absorption of iloperidone. The in vitro and in vivo studies revealed that JUC-C2 possessed an excellent dissolution behavior and improved pharmacokinetic profile.Crystal Growth & Design 11/2013; 13(12):5261–5266. DOI:10.1021/cg4010104 · 4.56 Impact Factor
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ABSTRACT: Cytochrome P450 (CYP) is a super family of phase I enzyme in the biotransformation of xenobiotics and medications. Most medications undergo deactivation by CYP, and then are eliminated through either bile or kidneys from the body. CYP isozymes play a crucial role in drug interactions that may result in enhanced toxicity, reduced efficacy or onset of adverse reactions. On the other hand, many agents affecting CYP expression and activity may alter metabolic rate of different medications co-administrated. Therefore, the molecular basis, regulation by inducers or inhibitors, and pharmacologic reaction of specific CYP isozymes are the key issues of biochemical mechanisms, pharmaceutical development and safe use of various medications. This book is to meet the needs from basic molecular biochemists, pharmacologists, pharmacists, medical students, clinical practitioners and scientists, as well as broad readers who wish to understand how an herbal extract, medication or natural supplement is metabolized or transformed in the liver or other sites for deactivation and elimination. Special focuses are paid to herbal extracts and medications in the treatment of neuro-psychiatric or cardiovascular disorders, diabetes and viral hepatitis. Detailed dissection of drug interactions in a particular field intends to provide rationales for useful guidance of safe drug use in daily practice. The contributing authors are basic scientists, pharmacists, pharmacologists and on-service physicians in cardiovascular, neuro-psychiatric, gastroenterologic and hepatologic fields from Europe (Germany, France, Portugal), Australia, the US and China. Thus, the book is the collection of master pieces by well-known experts from various regions of the world, and represents the current understanding of CYP enzyme reaction and a contemporary coverage of possible drug interactions in involved fields. The featured chapters are scientific elucidation of basic biochemistry, pharmacology and clinical investigations in the interest of drug metabolism, interaction and safe use guidance in the single focus of this microsomal enzyme with multi-facet metabolic function.First edited by Jian Wu, 09/2014; Nova Science Publishers, Inc.., ISBN: 978-1-61942-209-4