Prominently selective fluorescence approach with distinctive biopharmaceutical utility for analysis of lurasidone in human plasma and urine: Application to in vitro dissolution and content uniformity testing.

A relevant approach based on the attractive inherited merits of fluorescence spectroscopy has been established for quantitative estimation of a newly approved second-generation atypical antipsychotic lurasidone (LUR) in its raw materials and pharmaceutical dosage forms. This study brings to light the strong native fluorescence of LUR at 400 nm in water after excitation at 316 nm. Different experimental parameters that may compromise the fluorescence of the drug were carefully investigated and optimized. A linear response was established between the relative fluorescence intensity and concentration over the concentration range of 50-650 ng/mL with excellent correlation (r = 0.9998). The validity of the method was evidenced in accordance with International Council for Harmonization guidelines, with minimal detection and quantification limits of 2.88 and 8.73 ng/mL, respectively. The method was effectively applied for the estimation of LUR in spiked human plasma and urine samples with acceptable recoveries. The biopharmaceutical significance of the method was heightened by its successful applications for both content uniformity and in vitro dissolution testing. Three different tools accredited the greenness character of the presented study. Eco-friendliness, effortlessness, and cost effectiveness are crucial hallmarks of our study. The presented study demonstrates potential applicability in quality control laboratories with limited resources.

Development of LC-MS/MS method for quantification of Lurasidone using volumetric absorptive microsampling (VAMS); a comparative study between dried blood and plasma samples.

The ecological impact of biological, chemical, and analytical research practices, including toxic reagents and biohazardous waste, has led to the development of alternative sampling and extraction techniques for bioanalysis. Microsampling (sample volume < 50 µL) aligns with the 3Rs principle, allowing multiple sampling points from the same animal at different time points and improving animal welfare. A bioanalytical method was developed to investigate factors related to bioanalytical challenges and the implementation of microsampling techniques. An LC-MS/MS method for Volumetric Absorptive Microsampling (VAMS), 20 µL, was developed for quantifying Lurasidone using a liquid-liquid extraction technique. The method uses a C18, Phenomenex column for chromatographic separation and a mobile phase composition of Methanol, Acetonitrile, and Water with 0.1 % HFBA. The method was validated over a concentration range of 5.0 to 1200.0 ng/mL and achieved acceptable precision and accuracy. The recovery for analyte from VAMS was approximately 40% at four different concentrations and is consistent (%CV < 15), with no significant differences among HCT levels. The matrix factor ranged between 85.00 and 115.00 %, showing no substantial issues with reduced or enhanced signal. The stability data showed no significant degradation of LUR in VAMS samples when stored at room temperature for 15 days. The newly established method for Lurasidone confirmed the use of VAMS sampling method and its analysis on LC-MS/MS. Further, the data obtained from microsampling techniques was compared with conventional (plasma) technique, as proof-of-concept, and it confirms the agreement between the two methods. The study supports the advantages of microsampling in protecting the environment and animals while maintaining scientific judgement.

Sustained Impairment of Lurasidone Clearance After Discontinuation of Posaconazole: Impact of Obesity, and Implications for Patient Safety.

PURPOSE/BACKGROUND: The antipsychotic agent lurasidone (Latuda®) is metabolized by Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such as ketoconazole, posaconazole, and ritonavir) is contraindicated due to the risk of sedation and movement disorders from high levels of lurasidone. This study evaluated the time-course of recovery from the posaconazole drug interaction, and the effect of obesity on the recovery process. METHODS/PROCEDURES: Healthy normal-weight volunteers (n = 11, mean body mass index, BMI, = 23.1 kg/m) and otherwise healthy obese subjects (n = 13, mean BMI = 49.3 kg/m) received single doses of lurasidone in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. FINDINGS/RESULTS: With posaconazole coadministration, lurasidone area under the concentration curve (AUC) increased by an arithmetic mean factor of 6.2 in normals, and by 4.9 in obese subjects. Post-treatment washout of posaconazole was slow in normals (mean half-life 31 hours), and further prolonged in obese subjects (53 hours). Recovery of lurasidone AUC toward baseline was correspondingly slow, and was incomplete. AUC remained significantly elevated above baseline both in normals (factor of 2.1) and obese subjects (factor of 3.4) even at 2 weeks after stopping posaconazole. IMPLICATIONS/CONCLUSIONS: Product labeling does not address the necessary delay after discontinuation of a strong CYP3A inhibitor before lurasidone can be safely administered. We recommend requiring normal-weight and obese patients to limit the dosage of lurasidone, or undergo a washout period, for two and three weeks, respectively, after discontinuation of posaconazole.

Phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) as a dual solubilization approach for development of formulation with diminished food effect: Fast/fed in vivo pharmacokinetics study in human.

The novel self- nanoemulsifying self-nanosuspension (SNESNS) combines the advantages of two efficient solubilization technologies; the nanoemulsion and the nanosuspension. The aim of this study is to test the efficiency of phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) formulation as a powerful tool to diminish the food effect on bioavailability of lurasidone hydrochloride as BCS Class II model drug. Phospholipid was incorporated into SNESNS to increase the solubilization power of the in-situ formed nanoemulsion and facilitate the dispersion of the in-situ formed nanosized drug particles. P-SNESNS was evaluated for particle size, Polydispersity index, in vitro dissolution and transmission electron microscopy (TEM). The drug amount dissolved after water dilution of LSD p-SNESNS was ~2 folds that dissolved after dilution of non-phospholipid SNESNS. The self-nanosuspension obtained by aqueous dilution of p-SNESNS kept the cubic morphology of LSD macroparticles. The high in vitro dissolution of LSD in the non-sink dissolution media (water and Phosphate buffer pH6.8) indicated that the p-SNESNS formulation had successfully increased the drug solubility irrespective of pH of the medium. The pharmacokinetics parameters of LSD p-SNESNS in humans were the same in both the fasted and fed states and were similar to those of LSD capsules in the fed state. Our results propose that p-SNESNS could be promising to increase patient compliance and drug efficiency of BCS class II antipsychotics by diminishing the food effect on their oral absorption and preventing the necessity to administer them with food.

LC-MS/MS assay for the determination of lurasidone and its active metabolite, ID-14283 in human plasma and its application to a clinical pharmacokinetic study.

The authors proposed a sensitive, selective and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay procedure for the quantification of lurasidone and its active metabolite, i.e. ID-14283 in human plasma simultaneously using corresponding isotope labeled compounds as internal standards as per regulatory guidelines. After liquid-liquid extraction with tert-butyl methyl ether, the analytes were chromatographed on a C18 column using an optimized mobile phase composed of 5 mm ammonium acetate (pH 5.0) and acetonitrile (15:85, v/v) and delivered at a flow rate of 1.00 mL/min. The assay exhibits excellent linearity in the concentration ranges of 0.25-100 and 0.10-14.1 ng/mL for lurasidone and ID-14283, respectively. The precision and accuracy results over five concentration levels in four different batches were well within the acceptance limits. Lurasidone and ID-14283 were found to be stable in battery of stability studies. The method was rapid with the chromatographic run time 2.5 min, which made it possible to analyze 300 samples in a single day. Additionally, this method was successfully used to estimate the in vivo plasma concentrations of lurasidone and ID-14283 obtained from a pharmacokinetic study in south Indian male subjects and the results were authenticated by conducting incurred samples reanalysis. Copyright © 2015 John Wiley & Sons, Ltd.

Pharmacokinetics and Tolerability of Lurasidone in Children and Adolescents With Psychiatric Disorders.

PURPOSE: The aim of this study was to evaluate the pharmacokinetic (PK) profile and tolerability of lurasidone in children and adolescents with a range of psychiatric disorders. METHODS: This multicenter, open-label, single and multiple ascending-dose study of the PK profile of lurasidone (20, 40, 80, 120, and 160 mg/d) enrolled outpatients aged 6 to 17 years with a diagnosis of attention deficit/hyperactivity disorder, bipolar spectrum disorder, or other psychiatric disorder. Serial blood samples were collected for analysis of PK parameters, including Cmax, Tmax, and AUC0-24. FINDINGS: Exposure (Cmax and AUC0-24) to lurasidone and its active metabolites showed linear increases across the entire dose range. Slope estimates (95% CI) across the dose range studied was 0.90 ng · h/mL (0.74-1.06) for AUC0-24 and 0.70 ng/mL (0.52-0.87) for Cmax on day 10 or 12. Lurasidone exposure, after multiple-dose administration in this child and adolescent population, was similar to exposure observed at steady state in adults. The effects of dose on exposure to the 3 active metabolites of lurasidone were linear and similar after the administration of single and multiple doses. Adverse events were qualitatively similar to those reported in adults. Discontinuations due to adverse events were dose related, with doses <120 mg/d being better tolerated than higher doses, especially in younger children. IMPLICATIONS: In this child and adolescent population, exposure parameters for lurasidone and its active metabolites were dose proportional in the range of 20 to 160 mg/d after the administration of single and multiple doses. These results suggest that lurasidone doses <120 mg/d were better tolerated compared with higher doses, especially in younger children. ClinicalTrials.gov identifier: NCT01620060.