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: Since the 1970s, clinicians have increasingly become more familiar with hyperprolactinemia (HPRL) as a common adverse effect of antipsychotic medication, which remains the cornerstone of pharmacological treatment for patients with schizophrenia. Although treatment with second-generation antipsychotics (SGAs) as a group is, compared with use of the first-generation antipsychotics, associated with lower prolactin (PRL) plasma levels, the detailed effects on plasma PRL levels for each of these compounds in reports often remain incomplete or inaccurate. Moreover, at this moment, no review has been published about the effect of the newly approved antipsychotics asenapine, iloperidone and lurasidone on PRL levels. The objective of this review is to describe PRL physiology; PRL measurement; diagnosis, causes, consequences and mechanisms of HPRL; incidence figures of (new-onset) HPRL with SGAs and newly approved antipsychotics in adolescent and adult patients; and revisit lingering questions regarding this hormone. A literature search, using the MEDLINE database (1966-December 2013), was conducted to identify relevant publications to report on the state of the art of HPRL and to summarize the available evidence with respect to the propensity of the SGAs and the newly approved antipsychotics to elevate PRL levels. Our review shows that although HPRL usually is defined as a sustained level of PRL above the laboratory upper limit of normal, limit values show some degree of variability in clinical reports, making the interpretation and comparison of data across studies difficult. Moreover, many reports do not provide much or any data detailing the measurement of PRL. Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL. Considering the PRL-elevating propensity of the newly approved antipsychotics, evidence seems to indicate these agents have a PRL profile comparable to that of clozapine (asenapine and iloperidone), ziprasidone and olanzapine (lurasidone). PRL elevations with antipsychotic medication generally are dose dependant. However, antipsychotics having a high potential for PRL elevation (amisulpride, risperidone and paliperidone) can have a profound impact on PRL levels even at relatively low doses, while PRL levels with antipsychotics having a minimal effect on PRL, in most cases, can remain unchanged (quetiapine) or reduce (aripiprazole) over all dosages. Although tolerance and decreases in PRL values after long-term administration of PRL-elevating antipsychotics can occur, the elevations, in most cases, remain above the upper limit of normal. PRL profiles of antipsychotics in children and adolescents seem to be the same as in adults. The hyperprolactinemic effects of antipsychotic medication are mostly correlated with their affinity for dopamine D2 receptors at the level of the anterior pituitary lactotrophs (and probably other neurotransmitter mechanisms) and their blood-brain barrier penetrating capability. Even though antipsychotics are the most common cause of pharmacologically induced HPRL, recent research has shown that HPRL can be pre-existing in a substantial portion of antipsychotic-naïve patients with first-episode psychosis or at-risk mental state.CNS Drugs 03/2014; DOI:10.1007/s40263-014-0157-3 · 4.38 Impact Factor
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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