8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine.

INTRODUCTION: To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). METHODS: Seventy-nine Japanese psychiatric patients were treated with MIR for 1-8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. RESULTS: Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight-corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight-corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. DISCUSSION: The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats.

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.

Impact of the Omics-Based Biomarkers on the Mirtazapine's Steady-State Concentration, Efficacy and Safety in Patients with Affective Disorders Comorbid with Alcohol Use Disorder.

Introduction: Mirtazapine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with mirtazapine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective: The objective of this study was to investigate the effect of polymorphisms of the CYP3A4, CYP2C9, CYP3A5, ABCB1, CYP2C19, SCL6A4, and 5-HTR2A genes on the concentration/dose indicator of mirtazapine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder. Material and Methods: Our study included 108 patients with recurrent depressive disorder (average age - 35.2 ± 15.1 years). The treatment regimen included mirtazapine in an average daily dose of 45.0 [30.0; 60.0] mg per week. Therapy efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels, we performed the real-time polymerase chain reaction. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6b-HC/cortisol). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our study didn't reveal any statistically significant results in terms of the treatment efficacy and safety of the therapy. We also didn't reveal a statistical significance for the concentration/dose indicator of mirtazapine in patients with different genotypes. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the miR-27b plasma levels in patients with different genotypes. At the same time, correlation analysis didn't reveal a statistically significant relationship between the mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: rs = -0.2, p = 0.46. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.029, p = 0.93. In addition, we didn't reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: rs = -0,188, p = 0.85. However, the difference in the CYP3A enzymatic activity in carriers of AG and GG genotypes of the 6986A > G polymorphism of CYP3A5 gene has been revealed: (AG) 4.75 [1.28; 7.34] vs (GG) 8.83 [4.73; 13.62], p-value = 0.023. Conclusion: Thus, the effect of genetic polymorphism of the CYP3A4, CYP2C9, CYP2C9, CYP3A5, ABCB1, CYP2C19, CYP2C19, CYP2C19, SCL6A4, 5-HTR2A gene on the efficacy and safety profiles of mirtazapine was not demonstrated in a group of 108 patients with depressive disorder and alcohol use disorder.

The Influence of Concentration of Micro-RNA hsa-miR-370-3p and CYP2D6*4 on Equilibrium Concentration of Mirtazapine in Patients With Major Depressive Disorder.

Introduction: Mirtazapine is commonly prescribed to patients diagnosed with major depressive disorder.Some proportion of these patients do not show adequate response to treatment regimen containing mirtazapine, whereas many of them experience dose-dependent adverse drug reactions. Results of the previous studies showed that CYP2D6 is involved in the biotransformation of mirtazapine, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective: The objective of our study was to investigate the influence of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of mirtazapine, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma levelsin patients suffering from recurrent depressive disorder. Material and Methods: Our study included 192 patients with major depressive disorder (age - 41.4 ± 15.6 years). Treatment regimen included mirtazapine in an average daily dose of 37.4 ± 13.5 mg per week. Treatment efficacy was evaluated using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction. The activity of CYP2D6 was assessed with HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring (TDM) has been performed using HPLC-MS/MS. Results: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 10.0 [9.0; 11.0] and (GA) 12.0 [11.0; 12.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 4.0 [3.0; 5.0], p < 0.001. We didn't reveal a statistical significance for concentration/dose indicator of mirtazapine in patients with different genotypes: (GG) 0.229 [0.158; 0.468] and (GA) 0.290 [0.174; 0.526], p = 0.196. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 23.6 [17.6; 28.0], (GA) 21.8 [17.2; 27.0], p = 0.663. At the same time, correlation analysis didn't reveal a statistically significant relationship between the mirtazapine efficacy profile evaluated by changes in HAMD scale scores and the hsa-miR-370-3p plasma concentration: rs = 0.05, p = 0.460. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.11, p = 0.124. In addition, we revealed the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.32, p < 0.001. At the same time, correlation analysis revealed a statistically significant relationship between the mirtazapine concentration and the hsa-miR-370-3p plasma concentration: rs = 0.31, p < 0.001. Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of mirtazapine was demonstrated in a group of 192 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p remains a promising biomarker for assessing the level of CYP2D6 expression, because it correlates with encoded isoenzyme activity.

Development of mirtazapine loaded solid lipid nanoparticles for topical delivery: Optimization, characterization and cytotoxicity evaluation.

Mirtazapine, an antidepressant drug has been proved to exert antipruritic effect upon oral administration in numerous clinical trial studies. The objective of the current study was to develop mirtazapine loaded solid lipid nanoparticles (SLNs) and evaluate its potential as a topical drug delivery system for management of pruritus. Mirtazapine loaded SLNs were successfully developed and optimized applying Box-Behnken design. The optimized mirtazapine loaded SLNs were characterized for physicochemical parameters and morphology. The in vitro cytotoxicity and cellular uptake studies of optimized SLNs were performed in human epithelial A-431 cell line. Further, the optimized mirtazapine loaded SLNs dispersion was incorporated into gel and characterized for rheology and texture analysis. The particle size and PDI of optimized mirtazapine loaded was found to be 180.3 nm and 0.209 respectively. The cytotoxicity studies revealed the safety of mirtazapine loaded SLNs on topical administration. The developed gel showed pseudoplastic flow behavior and good textural profile. The in vitro drug release studies showed that the developed mirtazapine loaded SLNs dispersion and its gel followed Korsmeyer-Peppas model (R2 = 0.905) and Higuchi model (R2 = 0.928) respectively. The ex vivo drug permeation studies showed higher values for mean cumulative amount of drug released (548.25 ± 29.29 µg/cm2), permeation flux (45.10 ± 0.78 µg/cm2/h) and skin retention (11.33 ± 0.85%) of SLNs gel in comparison to pure drug gel. The stability studies indicate the stability of SLNs gel for three months at refrigerated and ambient temperatures. Therefore, abovementioned findings suggest that mirtazapine loaded SLNs could be a potential system for topical management of pruritus.

[Mirtazapine-Induced Mania: A Case Report]. / Mania Induzida por Mirtazapina: Um Caso Clínico.

Manic and hypomanic states associated with antidepressant treatments are relatively common; however, when specifically considering mirtazapine, those side effects are infrequent. The authors report a clinical case regarding a manic episode with dysphoric features in a patient with no personal or family previous psychiatric history. It began two weeks after starting treatment with mirtazapine up to 30 mg/day. This episode was treated discontinuing mirtazapine and initiating olanzapine (10 mg), with symptomatic remission. Mirtazapine has a specific pharmacodynamics, blocking not only post-synaptic serotonergic receptors but also α2-presynaptic adrenergic receptors. Taking this into consideration, it was hypothesized that this case could be attributed to a noradrenergic syndrome, characterized by dysphoria, irritability, insomnia and psychomotor agitation.

O desenvolvimento de estados maníacos e hipomaníacos associado ao uso de antidepressivos é relativamente comum. Contudo, no caso da mirtazapina, este é um efeito secundário raro. Os autores descrevem um caso clínico de um episódio maníaco de características disfóricas, num doente sem antecedentes psiquiátricos pessoais ou familiares, com instalação duas semanas após início de tratamento com mirtazapina até 30 mg/dia. Uma vez suspensa a mirtazapina e iniciada olanzapina (10 mg) verificou-se remissão sintomática. A mirtazapina apresenta uma farmacodinâmica particular, sendo antagonista não só de recetores serotoninérgicos póssinápticos, mas também de recetores adrenérgicos pré-sinápticos α2. Neste sentido, colocou-se a hipótese de se tratar de uma síndrome noradrenérgica, caracterizada por disforia, irritabilidade, insónia e agitação psicomotora.

A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration-QTc (C-QTc) Analysis.

Most new chemical entities with systemic availability are required to be tested in a study specifically designed to exclude drug-induced corrected QT interval (QTc) effects, the so-called thorough QT/QTc study. Mirtazapine (Remeron™) is an antidepressant indicated for the treatment of episodes of major depression, which was originally approved in 1994 without a thorough QT study. To evaluate the proarrhythmic potential of mirtazapine, we performed a QT/QTc study with a novel design including implementation of an analysis of the relationship between drug concentration and the QTc interval as the primary assessment of proarrhythmic potential of mirtazapine. The least squares mean differences of the corrected QT interval between mirtazapine and placebo at the geometric mean maximum concentration of drug in blood plasma (90% confidence interval) were 2.39 milliseconds (0.70, 4.07) at the 45-mg dose and 4.00 milliseconds (1.18, 6.83) at the 75-mg dose level of mirtazapine. Modeling of the concentration/QTc relationship for moxifloxacin confirmed that the assay method was adequately sensitive. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45-mg and 75-mg doses of mirtazapine was not at a level generally considered to be clinically meaningful. This study further demonstrates that analysis of the relationship between drug concentration and the QTc interval may be a reasonable alternative to traditional TQT studies to assess risk of QT prolongation.

In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease.

BACKGROUND: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats. HYPOTHESIS/OBJECTIVES: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats. ANIMALS: Eleven LD and 11 age-matched control cats. METHODS: Case-control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half-life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD. RESULTS: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1-4] hours versus 1 [1-4] hours; P = .03). The calculated half-life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9-61.4] hours versus 7.4 [6.7-9.1] hours; P < .002). Mirtazapine half-life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (-0.0022 min-1 , CI: -0.0050 to 0.00054 min-1 ) and cats without LD (0.01849 min-1 , CI: -0.025 to -0.012 min-1 ; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with LD might require less frequent administration of mirtazapine than normal cats.