Safety, Tolerability, and Effect of Food on the Pharmacokinetics of Iloperidone (HP 873), a Potential Atypical Antipsychotic

Sainati, Stephen; Hubbard, John W.; Chi, Eric; Grasing, Kenneth; Brecher, Martin

doi:10.1002/j.1552-4604.1995.tb04112.x

Cited by 45 publications

(32 citation statements)

References 6 publications

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“…Although NMS has more likely been associated to the use of 'typical' high potency antipsychotics (i.e. haloperidol), cases of NMS have been also described with each atypical AP [80,107]. It has been reported following the use of risperidone [170], olanzapine [124], iloperidone [108], clozapine [80], asenapine [171] and aripiprazole [172].…”

Section: Resultsmentioning

confidence: 98%

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An update of safety of clinically used atypical antipsychotics

Orsolini

Tomasetti

Valchera

et al. 2016

Expert Opinion on Drug Safety

121

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A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.

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Section: Resultsmentioning

confidence: 98%

“…Dizziness/dry mouth/nasal congestion/somnolence/fatigue/tachycardia are the most commonly reported AEs [107].…”

Section: Adverse Effectsmentioning

confidence: 99%

An update of safety of clinically used atypical antipsychotics

Orsolini

Tomasetti

Valchera

et al. 2016

Expert Opinion on Drug Safety

121

View full text Add to dashboard Cite

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“…These trials were performed on patients that met the DSM-III/IV criteria for schizophrenia, and Fanapt was shown to be superior to the placebo in these trials. Unlike most other atypical antipsychotics, Fanapt displayed a superior side effect profile with the most common adverse reactions being dizziness, somnolence, and hypotension; further studies indicated that coadministration with food decreased the severity of these reactions (3).…”

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confidence: 93%

ACS Chemical Neuroscience Molecule Spotlight on Fanapt

Hopkins

2010

ACS Chem. Neurosci.

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The new mixed dopamaine D 2 /serotonin 5-HT 2A antagonist, Fanapt (iloperidone), was approved by the FDA on May 6th, 2009 for the treatment of schizophrenia in adults. (1, 2). Schizophrenia is a chronic, severe, and debilitating mental disorder that affects approximately 2.4 million Americans, around 1.1% of the population. The net cost of this disorder is staggering as estimates from 2002 reveal this disorder to cost $62.7 billion. A major issue with the treatment of schizophrenia is that patients show varying levels of response and tolerance to available therapies. Although the symptoms of the disease are very severe, estimates show that approximately 3 out of 4 patients discontinue medication prior to completing 18 months of treatment, many times due to the severe side effects of the approved medications.Fanapt (iloperidone) is a monoamine and acts by antagonizing dopamine and serotonin receptor subtypes, noradrenaline (R 2C ), dopamine (D 2 and D 3 ), and serotonin (5-HT 1A and 5-HT 6 ). The efficacy of Fanapt was demonstrated in two placebo-controlled short-term (4-and 6-week) trials. These trials were performed on patients that met the DSM-III/IV criteria for schizophrenia, and Fanapt was shown to be superior to the placebo in these trials. Unlike most other atypical antipsychotics, Fanapt displayed a superior side effect profile with the most common adverse reactions being dizziness, somnolence, and hypotension; further studies indicated that coadministration with food decreased the severity of these reactions (3).Fanapt has traveled a circuitous route to approval. Originally, it was disclosed by Hoechst Marion Roussel in 1995 as a novel atypical antipsychotic agent (2), and soon after, HMR sold the research rights to Titan Pharmaceuticals. After obtaining the rights the previous year, Titan Pharmaceuticals then handed over the worldwide rights to Novartis Pharmaceuticals in 1998, which in turn turned over the phase III development rights to Vanda Pharmaceuticals in 2004.Unfortunately, the much traveled drug did not have a smooth route to approval. In fact, in 2008, the FDA issued a "not approvable letter" to Vanda Pharmaceuticals (4) for iloperidone even though the company demonstrated effectiveness in a 3101 study (4) that was published in December 2006 and demonstrated that iloperidone was superior to placebo in a prior study. In the letter, the FDA indicated that it would require an additional clinical trial comparing iloperidone to placebo and an additional comparator, plus additional safety data for the 20 and 24 mg/kg doses. Not even a year after the company received the "not approvable letter", the FDA approved Fanapt (tablets) to treat adults with schizophrenia. After nearly 15 years of research, rights transfers, and clinical trials, Novartis recently announced that Fanapt tablets are now available across the U.S. as a twice-daily, oral antipsychotic (5).

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“…Iloperidone undergoes extensive pre-systemic elimination and is cleared through multiple metabolic pathways that include O-dealkylation, hydroxylation, decarboxylation/ oxidation and reduction [4,5] . Two major metabolites of iloperidone (M 1 , also termed P-88 and M 2 , also termed P-95) have higher plasma concentrations in humans than iloperidone, although the exact fractions of M 1 and M 2 formation from the parent iloperidone have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis

Pei

Huang

et al. 2016

Acta Pharmacol Sin

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Aim: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6*10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients. Methods: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M 1 (P-88) and M 2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites. Results: Patients with the CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M 1 , and lower concentrations of M 2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M 1 (K 23 ) and M 2 (K 24 ). The K 23 value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K 24 value of the patients with C/T and T/T genotypes was 0.693-and 0.492-fold, respectively, as low as that of the patients with C/C genotype. Conclusion: CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.

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Safety, Tolerability, and Effect of Food on the Pharmacokinetics of Iloperidone (HP 873), a Potential Atypical Antipsychotic

Cited by 45 publications

References 6 publications

An update of safety of clinically used atypical antipsychotics

An update of safety of clinically used atypical antipsychotics

ACS Chemical Neuroscience Molecule Spotlight on Fanapt

Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis

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