Effect of feeding on the pharmacokinetics of vilazodone in dogs.

Vilazodone (VLZ) is a drug approved for the treatment of major depressive disorder in humans but no data are available for dogs. The present study aimed to evaluate the pharmacokinetics of a single oral 40 mg dose of VLZ in healthy Labrador dogs (n = 6) in fasted and fed conditions. Dogs were randomly divided in two (n = 3) groups in a cross-over study design (2 × 2). Group I was administered with VLZ at 40 mg/dog after fasting over-night. Group II was fed prior to and after administration of the same dose. A two-week wash-out period was observed. Plasma samples collected underwent LC-MS/MS analysis. VLZ concentrations were quantified in dogs' plasma in two different windows of time: 30 min to 10 h for the fasted group and 4 h to 35 h for the fed group. The values for t1/2λz were statistically different between the groups (fed, 4.6 ±â€¯1.1 h vs fasted, 1.7 ±â€¯0.2 h). Tmax drastically changed between the groups (fed, 10 h vs fasted, 1.5 h), while Cmax did not significantly vary (fed, 39.4 ±â€¯5.6 ng/mL vs fasted, 38.7 ±â€¯4.8 ng/mL). The AUC value was always statistically higher in the fed group. As a result, the average relative oral fasted bioavailability of VLZ was low, 28.8 ±â€¯6.1%. In conclusion, feeding can affect the pharmacokinetics of VLZ in the dog.

Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation.

Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 ± 0.708 µM), 5-HT1A agonist (EC50 = 107 ± 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 ± 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.

UPLC-MS-MS Method for the Determination of Vilazodone in Human Plasma: Application to a Pharmacokinetic Study.

A sensitive, rapid and simple liquid chromatographic-electrospray ionization tandem mass spectrometric (LC-ESI-MS-MS) method was developed for the quantitative determination of vilazodone in human plasma and for the study of the pharmacokinetic behavior of vilazodone in healthy Egyptian volunteers. With escitalopram as internal standard (IS), liquid-liquid extraction was used for the purification and preconcentration of analytes from human plasma matrix using diethyl ether. The separation was performed on an Acquity UPLC BEH shield RP C18 column (1.7 µm, 2.1 × 150 mm). Isocratic elution was applied using methanol-0.2% formic acid (90:10, v/v). Detection was performed on a triple-quadrupole tandem mass spectrometer with multiple reaction monitoring mode via an electrospray ionization source at m/z 442.21 → 155.23 for vilazodone and m/z 325.14 → 109.2 for escitalopram. Linear calibration curves were obtained over the range of 1-200 ng/mL with the lower limit of quantification at 1 ng/mL. The intra- and inter-day precision showed relative standard deviation ≤3.3%. The total run time was 1.5 min. This method was successfully applied for clinical pharmacokinetic investigation, and a preliminary metabolic study was also carried out.

P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood-brain barrier in vivo.

P-glycoprotein (P-gp)-mediated brain efflux of xenobiotics is a well-known process, which may result in suboptimal target engagement and consequently reduced efficacy of drugs exerting their therapeutic effects in the central nervous system. In the present study the role of P-gp in transport across the blood-brain barrier (BBB) was investigated with a series of newer antidepressants (levomilnacipran, vilazodone and vortioxetine) and a control substrate (escitalopram) using P-gp knock-out (KO) and P-gp competent wild-type (WT) mice. Brain and plasma exposure time-courses were measured after an acute subcutaneous dose and at steady-state obtained after subcutaneous drug infusion by osmotic minipumps. Following acute dosing, the brain-to-plasma KO/WT exposure enhancement ratios ((AUCbrain ko/AUCplasma ko)/(AUCbrain WT/AUCplasma WT)) were 5.8 (levomilnacipran), 5.4 (vilazodone), 3.1 (escitalopram) and 0.9 (vortioxetine), respectively. At steady-state, assessment of Kp,uu (unbound brain concentrations/unbound plasma concentrations) revealed a restriction in the brain distribution in WT mice for all compounds except vortioxetine. Levomilnacipran exhibited the most pronounced efflux with a Kp,uu-value of 0.038 in WT mice which was increased to 0.37 in KO mice. Based on both the acute and steady-state distribution data, the results suggest that levomilnacipran, vilazodone and escitalopram are susceptible to P-gp mediated efflux at the BBB in vivo in mice, whereas vortioxetine was practically devoid of being affected by P-gp in vivo. The functional impact of the drug transport-controlling role of P-gp at the BBB was demonstrated by in vivo cortical serotonin transporter occupancy of vilazodone, which exhibited a 20-fold higher plasma EC50 in WT mice compared to KOs.

Vilazodone: a review in major depressive disorder in adults.

Vilazodone (Viibryd(®)) exhibits the combined properties of a selective serotonin reuptake inhibitor (SSRI) and a serotonin 5-HT1A receptor partial agonist, and is approved in the US for the treatment of major depressive disorder (MDD) in adults. In four randomized, double-blind, clinical trials, oral vilazodone 20 or 40 mg once daily for 8 or 10 weeks reduced from baseline (improved) the Montgomery-Åsberg Depression Rating Scale (MADRS) total score significantly more than placebo in adult patients with MDD. In these trials, significantly greater reductions in MADRS total score with vilazodone compared with placebo were seen from either week 1, week 2 (two trials) or week 6. In a noncomparative study, MADRS total scores continued to improve throughout therapy for up to 1 year. Vilazodone was generally well tolerated, with the most common treatment-emergent adverse events being mild or moderate diarrhoea, nausea and headache. Vilazodone had only limited adverse effects on sexual function or bodyweight. Therefore, vilazodone is an effective agent for treating MDD in adults.

A simple and fast UHPLC-MS-MS assay for rapid determination of vilazodone in plasma sample.

Vilazodone is a novel antidepressant agent, approved by the US Food and Drug Administration (US FDA) for the treatment of major depressive disorder. In this study, a fast sensitive ultra-high performance liquid chromatography-tandem mass spectroscopy method was developed and validated for the determination of vilazodone in human plasma. After a simple protein precipitation by acetonitrile, both vilazodone and risperidone (internal standard, IS) were separated on an Acquity UPLC BEH™ C18 column (50 × 2.1 mm, 1.7 µm). An isocratic mobile phase of acetonitrile:10 mM ammonium acetate (80:20, v/v) was used at the 0.3 mL/min flow rate. Both vilazodone and IS were eluted at 0.44 and 0.47 min, respectively, having a run time of 1.0 min. Detection and quantification were performed using an electrospray ionization source in positive mode by multiple reaction monitoring. The precursor to product ion transitions were monitored at m/z 442.19 > 154.99 for vilazodone and m/z 411.18 > 191.07 for IS, respectively. The standard curve (0.40-500 ng/mL) was found to be linear with a lower limit of quantification 0.40 ng/mL. All validation results were found to be within acceptable limits as per guidelines for bioanalytical method validation (US FDA and European Medicines Agency). To the best of our knowledge, this is the first fully validated assay for the determination of vilazodone in human plasma and was successfully applied to an oral pharmacokinetic study in rats.

Pharmacokinetics and Safety of Vilazodone in Hepatic Impairment.

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder, is extensively hepatically metabolized. The pharmacokinetics, tolerability, and safety of vilazodone were investigated in 2 trials comparing participants with hepatic impairment with healthy controls. In these phase 1, open-label, parallel-group, single-dose pharmacokinetic studies, vilazodone (20 mg) was administered to participants with mild, moderate, or severe hepatic impairment or individually matched healthy controls. Vilazodone and M17 (the major metabolite) concentrations in plasma were analyzed using validated liquid chromatography with tandem mass spectrometry. Forty-eight participants (8 each in mild, moderate, and severe hepatic impairment groups with matched healthy controls) were evaluated for pharmacokinetic analyses. All pharmacokinetic parameters in participants with mild and moderate hepatic impairment were similar to those in healthy controls. Mean Cmax and AUC0-∞ were approximately 29% and 17% lower in participants with severe hepatic impairment compared with healthy participants; values for Tmax, and t1/2 were similar between groups. Diarrhea was experienced by more participants with hepatic impairment than controls (10 vs. 5, respectively), and vomiting (4 participants) occurred only in participants with severe hepatic impairment; other adverse events were roughly equivalent between groups. Following a single, 20-mg oral dose of vilazodone, pharmacokinetics were similar in participants with mild, moderate, or severe hepatic impairment and healthy controls. No dose adjustment is needed for patients with major depressive disorder who have mild, moderate, or severe hepatic impairment.

Influence of CYP3A4 induction/inhibition on the pharmacokinetics of vilazodone in healthy subjects.

PURPOSE: Vilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP-mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone. METHODS: Participants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded. FINDINGS: In study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated. IMPLICATIONS: These results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.).