ABSTRACT
Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of - 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (131I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.
Subject(s)
Administration, Intranasal , Brain , Lipids , Mirtazapine , Nanocapsules , Animals , Mirtazapine/pharmacokinetics , Mirtazapine/administration & dosage , Mirtazapine/chemistry , Brain/metabolism , Tissue Distribution , Nanocapsules/chemistry , Lipids/chemistry , Lipids/pharmacokinetics , Lipids/administration & dosage , Male , Mice , Drug Delivery Systems , Particle Size , Iodine Radioisotopes/pharmacokinetics , Iodine Radioisotopes/administration & dosage , Nasal Mucosa/metabolism , Mianserin/pharmacokinetics , Mianserin/administration & dosage , Mianserin/chemistry , Mianserin/analogs & derivatives , Mianserin/bloodABSTRACT
The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile, whereas only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces was derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human absorption, distribution, metabolism, and excretion study, in which the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study in which 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared with rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at a high level in PXB-mice, but they were either minimally observed or not observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict the potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand the biliary clearance mechanism of a drug. SIGNIFICANCE STATEMENT: Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared with preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help illustrate the human biliary clearance mechanism of a drug.
Subject(s)
Hepatobiliary Elimination , Liver/metabolism , Animals , Bile/metabolism , Biotransformation , Carbamates/administration & dosage , Carbamates/pharmacokinetics , Cyproheptadine/administration & dosage , Cyproheptadine/pharmacokinetics , Drug Evaluation, Preclinical/methods , Hepatocytes/metabolism , Hepatocytes/transplantation , Humans , Liver/cytology , Loratadine/administration & dosage , Loratadine/analogs & derivatives , Loratadine/pharmacokinetics , Male , Mianserin/administration & dosage , Mianserin/pharmacokinetics , Mice , Transplantation Chimera/metabolismABSTRACT
Mirtazapine is one of antidepression which is used mainly in the treatment of depression, moreover, it is sometimes used in the treatment of anxiety disorders, insomnia, nausea, and vomiting, and to produce weight gain when desirable. The action of mirtazapine is an antagonist of certain adrenergic and serotonin receptors, and, furthermore, the drug is used strong as antihistamine, and it is occasionally defined as a noradrenergic and specific serotonergic antidepressant (NaSSA). The comprehensive profile of mirtazapine gives more detailed information about nomenclature, formulae, elemental analysis, and appearance. In addition, the numerous methods of drug synthesis are summarized. Also the profile covers the physicochemical properties as: the value of pKa, drug solubility, melting point, X-ray powder diffraction, and analysis methods for example: (compendial, electrochemical, spectroscopic, and method of chromatographic). Besides that, the profile covered pharmacological profile and clinical pharmacokinetics in subtitle's (absorption, distribution, metabolism, and elimination). About 100 references were given as a proof of the above-mentioned studies.
Subject(s)
Adrenergic alpha-Antagonists/chemistry , Antidepressive Agents, Tricyclic/chemistry , Mianserin/analogs & derivatives , Serotonin Antagonists/chemistry , Adrenergic alpha-Antagonists/pharmacokinetics , Animals , Antidepressive Agents, Tricyclic/pharmacokinetics , Biological Availability , Biotransformation , Drug Compounding , Drug Stability , Humans , Mianserin/chemistry , Mianserin/pharmacokinetics , Mirtazapine , Serotonin Antagonists/pharmacokinetics , Technology, Pharmaceutical/methodsABSTRACT
INTRODUCTION: Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study. MATERIALS AND METHODS: Coacervation technique using Eudragit® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined. RESULTS AND DISCUSSION: The disintegration time of the SGF were found as A1 < A2 < A3 < A5 < A4 (8% Eudragit® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab. CONCLUSIONS: According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit® E-100) formulations could be promising alternatives to Remeron SolTab.
Subject(s)
Acrylates/chemistry , Antidepressive Agents, Tricyclic/administration & dosage , Excipients/chemistry , Mianserin/analogs & derivatives , Polymers/chemistry , Administration, Oral , Antidepressive Agents, Tricyclic/chemistry , Antidepressive Agents, Tricyclic/pharmacokinetics , Caco-2 Cells , Drug Compounding , Drug Liberation , Humans , Mianserin/administration & dosage , Mianserin/chemistry , Mianserin/pharmacokinetics , Mirtazapine , Solubility , Tablets , TasteABSTRACT
BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording.
Subject(s)
Antidepressive Agents, Second-Generation/blood , Cyclohexanols/blood , Desvenlafaxine Succinate/blood , Doxepin/blood , Mianserin/analogs & derivatives , Venlafaxine Hydrochloride/blood , Adult , Antidepressive Agents, Second-Generation/pharmacokinetics , Antidepressive Agents, Second-Generation/therapeutic use , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Databases, Factual , Desvenlafaxine Succinate/pharmacokinetics , Desvenlafaxine Succinate/therapeutic use , Doxepin/pharmacokinetics , Doxepin/therapeutic use , Drug Monitoring , Drug Therapy, Combination , Female , Humans , Male , Mianserin/blood , Mianserin/pharmacokinetics , Mianserin/therapeutic use , Middle Aged , Mirtazapine , Polypharmacy , Venlafaxine Hydrochloride/pharmacokinetics , Venlafaxine Hydrochloride/therapeutic useABSTRACT
A 40-year-old woman with bipolar disorder who was taking mirtazapine presented with mydriasis, abnormal diaphoresis, myoclonus and muscle rigidity after taking metocloplamide. Her medical history, which included the use of serotonergic agents, and the presence of symptoms including myoclonus and muscle rigidity were consistent with a diagnosis of serotonin syndrome (SS) according to the Hunter criteria. The symptoms diminished following three days of treatment with oral lorazepam and cyproheptadine and a reduced dose of mirtazapine. Metoclopramide is frequently used to various gastric symptom. Metoclopramide is not widely known to induce SS. This potentially fatal condition should be avoided by exercising care in the use of drugs that have the potential to cause drug-drug interactions.
Subject(s)
Antiemetics/pharmacology , Metoclopramide/pharmacology , Mianserin/analogs & derivatives , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Serotonin Syndrome/chemically induced , Adult , Bipolar Disorder/drug therapy , Drug Interactions , Female , Humans , Mianserin/pharmacokinetics , Mianserin/therapeutic use , Mirtazapine , Selective Serotonin Reuptake Inhibitors/therapeutic useABSTRACT
Objectives The objective of this study was to measure drug exposure and clinical effects after administration of transdermal mirtazapine (TMZ) in healthy cats. Methods Phase I: seven healthy research cats received (1) 3.75 mg and 7.5 mg TMZ once aurally with 48 h serum sampling (serum samples were obtained via the jugular catheter at 0, 0.5, 1, 2, 5, 9, 12, 24, 36 and 48 h); (2) 7.5 mg TMZ and placebo daily aurally for 6 days then 48 h serum sampling; (3) 1.88 mg mirtazapine orally once with serum sampling at 1, 4 and 8 h. Phase II: 20 client-owned cats were enrolled in a randomized, double-blind, placebo-controlled, three-way crossover clinical effect study. Treatments consisted of 6 days of aural 7.5 mg TMZ or placebo gel at home, and 1.88 mg mirtazapine orally once in the clinic. Owners documented appetite, rate of food ingestion, begging activity and vocalization daily at home. On day 6, food consumed, activity and vocalization were documented in hospital, and trough and peak serum mirtazapine levels were obtained. Serum mirtazapine and gel concentrations were measured using liquid chromatography/tandem mass spectrometry. Results Phase I: administration of TMZ achieved measureable serum mirtazapine concentrations. Area under the curve0-48 of multidose 7.5 mg TMZ was significantly higher than single-dose 1.88 mg oral mirtazapine (OMZ) ( P = 0.02). Phase II: client-owned cats administered TMZ had a significant increase in appetite ( P = 0.003), rate of food ingestion ( P = 0.002), activity ( P = 0.002), begging ( P = 0.002) and vocalization ( P = 0.002) at home. In hospital there was a significant increase in food ingested with both TMZ and OMZ compared with placebo ( P <0.05). Gel concentrations ranged from 87%-119% of target dose. Conclusions and relevance TMZ 7.5 mg daily achieves measureable serum concentrations and produces significant appetite stimulation despite variance in compounded gel concentrations, but side effects denote a lower dose is indicated.
Subject(s)
Cats/physiology , Mianserin/analogs & derivatives , Administration, Cutaneous , Animals , Appetite/drug effects , Cats/metabolism , Cross-Over Studies , Double-Blind Method , Mianserin/administration & dosage , Mianserin/blood , Mianserin/pharmacokinetics , Mirtazapine , Pilot ProjectsABSTRACT
abstract Ultraviolet spectrophotometric (UV) and Liquid Chromatographic (LC) methods for the determination of mianserin hydrochloride in pharmaceutical formulation were developed and validated. The various parameters, such as specificity, linearity, precision and accuracy were studied according to International Conference on Harmonization (ICH, 2005). For UV method, mianserin hydrochloride was determinate at 278 nm using HCl 0.1 M as the solvent. The response was linear in the concentration range of 20.0 - 140.0 µg/mL (r = 0.9998). Precision data evaluated by relative standard deviation was lower than 2%. The UV method was simple, rapid and low cost. Chromatographic analyses were performed in an Ace C18 column and the mobile phase was composed of methanol, 50 mM monobasic potassium phosphate buffer and 0.3% triethylamine solution adjusted to pH 7.0 with phosphoric acid 10% (85:15). LC method was specific, linear, precise, exact and robust. The results confirmed that the both methods are valid and useful to the routine quality control of mianserin hydrochloride in coated tablets. Statistical analysis by Student´s t-test showed no significant difference between the results obtained by UV and LC methods.
resumo Os métodos por espectrofotometria na região do ultravioleta (UV) e por cromatografia líquida (CL) para determinação do cloridrato de mianserina na forma farmacêutica foram desenvolvidos e validados. Os vários parâmetros, como especificidade, linearidade, precisão e exatidão foram avaliados de acordo com o International Conference on Harmonization (ICH, 2005). Para o método de UV, o cloridrato de mianserina foi determinado utilizando o comprimento de onda de 278 nm e HCl 0,1 M como solvente. A resposta foi linear na faixa de concentração de 20,0 a 140,0 µg/Ml (r = 0,9998). A precisão foi avaliada pelo valor de desvio padrão relativo (DPR) inferior a 2%. O método por UV é simples, rápido e de baixo custo. As análises cromatográficas foram realizadas em uma coluna Ace C18 e a fase móvel foi composta por metanol, tampão fosfato de potássio monobásico 50 mM com 0,3% de trietilamina com o pH ajustado para 7,0 com ácido fosfórico 10% (85:15). O método de CL foi específico, linear, preciso, exato e robusto. Os resultados confirmam que ambos os métodos são válidos e úteis para o controle de qualidade do cloridrato de mianserina em comprimidos revestidos. A análise estatística por teste t de Student não mostrou diferença significativa entre os resultados obtidos para os métodos de UV e CL.
Subject(s)
Spectrophotometry, Ultraviolet , Mianserin/pharmacokinetics , Tablets/pharmacokinetics , /analysis , Chromatography, LiquidABSTRACT
OBJECTIVE: Our study aimed to investigate the effect of mirtazapine on bone metabolism in the orchidectomized rat model. METHODS: Rats were divided into three groups. A sham-operated control group (SHAM group) and a control group after orchidectomy (ORX group) received the standard laboratory diet (SLD). An experimental group after orchidectomy (ORX MIRTA group) received SLD enriched with mirtazapine for 12 weeks. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone marker concentrations of osteoprotegerin (OPG), amino-terminal propeptide of procollagen type I, bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 were examined in bone homogenate. The femurs were used for biomechanical testing. RESULTS: Compared with the control ORX group, we found a lower BMD in the ORX MIRTA group. The differences were statistically significant, although not in the lumbar vertebrae. BMD was lower in the MIRTA group, suggesting a preferential effect on cortical bone. However, although the thickness of the diaphyseal cortical bone was not different, the fragility in the femoral neck area was statistically significantly different between the groups in biomechanical testing. Regarding the bone metabolism markers, there was a significant decrease in OPG and BALP levels, suggesting a reduction in osteoid synthesis. CONCLUSIONS: The results suggest that prolonged use of mirtazapine may have a negative effect on the synthesis of bone and on its mechanical strength, especially in the femoral neck. Further studies are warranted to establish whether mirtazapine may have a clinically significant adverse effect on bone exclusively in the model of gonadectomized rats, or whether the effect occurs also in the model of gonadally intact animals and in respective human models.
Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Antidepressive Agents, Tricyclic/pharmacology , Bone and Bones/drug effects , Mianserin/analogs & derivatives , Adrenergic alpha-Antagonists/blood , Adrenergic alpha-Antagonists/pharmacokinetics , Alkaline Phosphatase/metabolism , Animals , Antidepressive Agents, Tricyclic/blood , Antidepressive Agents, Tricyclic/pharmacokinetics , Biomechanical Phenomena , Bone Density/drug effects , Bone and Bones/metabolism , Bone and Bones/physiology , Compressive Strength , Male , Mianserin/blood , Mianserin/pharmacokinetics , Mianserin/pharmacology , Mirtazapine , Orchiectomy , Osteoprotegerin/metabolism , Rats, WistarABSTRACT
A simple, rapid and sensitive chiral capillary zone electrophoresis coupled with acetonitrile-field-amplified sample stacking method was developed that allows the simultaneous enantioselective separation of the mirtazapine, N-demethylmirtazapine, 8-hydroxymirtazapine and mirtazapine-N-oxide. The separation was achieved on an uncoated 40.2 cm×75 µM fused silica capillary with an applied voltage of 16 kV. The electrophoretic analyses were carried out in 6.25 mM borate-25 mM phosphate solution at pH 2.8 containing 5.5 mg/mL carboxymethyl-ß-cyclodextrin. The detection wavelength was 200 nm. Under these optimized conditions, satisfactory chiral separations of four pair enantiomers were achieved in less than 7 min in vitro. After one step clean-up liquid-liquid extraction using 96-well format, sample was introduced capillary zone electrophoresis with acetonitrile-field-amplified sample stacking to enhance the sensitivity of enantiomers. The method was validated with respect to specificity, linearity, lower limit of quantitation, accuracy, precision, extraction recovery and stability. The lower limit of quantification was 0.5 ng/mL with linear response over the 0.5-50 ng/mL concentration range for each mirtazapine, N-demethylmirtazapine and 8-hydroxymirtazapine enantiomer. The developed and validated method has been successfully applied to the enantioselective pharmacokinetic studies in 12 healthy volunteers after oral administration of rac- mirtazapine.
Subject(s)
Antidepressive Agents, Tricyclic/blood , Chemical Fractionation/methods , Electrophoresis, Capillary/methods , Mianserin/analogs & derivatives , Acetonitriles/chemistry , Administration, Oral , Antidepressive Agents, Tricyclic/pharmacokinetics , Biotransformation , Buffers , Cyclic N-Oxides/blood , Humans , Limit of Detection , Male , Mianserin/blood , Mianserin/pharmacokinetics , Mirtazapine , Reproducibility of Results , Stereoisomerism , beta-Cyclodextrins/chemistryABSTRACT
Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre- and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre- and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre- and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.
Subject(s)
Anti-Arrhythmia Agents/poisoning , Antidepressive Agents, Second-Generation/poisoning , Disopyramide/poisoning , Mianserin/poisoning , Anti-Arrhythmia Agents/analysis , Anti-Arrhythmia Agents/pharmacokinetics , Antidepressive Agents, Second-Generation/analysis , Antidepressive Agents, Second-Generation/pharmacokinetics , Bile/chemistry , Disopyramide/analysis , Disopyramide/pharmacokinetics , Female , Forensic Toxicology , Gastrointestinal Contents/chemistry , Humans , Mianserin/analysis , Mianserin/pharmacokinetics , Postmortem Changes , Suicide , Tissue Distribution , Young AdultABSTRACT
RATIONALE: Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative effects. The affinities of various antidepressants for histamine receptors have only been partially determined in vitro and animal study. Positron emission tomography (PET) can clarify the in vivo dynamics of antidepressants at histamine receptors. OBJECTIVES: We performed human PET imaging with [¹¹C]doxepin, a selective PET ligand of the histamine H1 receptor (H1R), to study the in vivo affinities of fluvoxamine and mirtazapine for the H1R. METHODS: The subjects were five male healthy Japanese volunteers. We performed cross-randomized PET imaging after single oral administration of fluvoxamine (25mg), mirtazapine (15 mg), or placebo. PET data were analyzed by region-of-interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations, using liquid chromatography/tandem mass spectrometry and subjective sleepiness. RESULTS: The binding potential ratio of mirtazapine in brain cortex was significantly lower than that of fluvoxamine or placebo. Fluvoxamine did not occupy the H1R, whereas H1R occupancy (H1RO) of mirtazapine reached 80-90 % in the cerebral neocortex. In the voxel-by-voxel analysis, the binding potential of mirtazapine was significantly lower than placebo in the dorsolateral prefrontal cortex, lateral temporal cortex, anterior cingulate gyrus, and posterior cingulate gyrus. The H1RO of mirtazapine depended on the plasma drug concentration (AUC(0-180 min)) and was related to subjective sleepiness. CONCLUSIONS: Our results demonstrate a low affinity of fluvoxamine and a very high affinity of mirtazapine for the human brain H1R in vivo. This study provides a basis for investigating the efficacy of new-generation antidepressants in central histamine systems.
Subject(s)
Fluvoxamine/pharmacology , Mianserin/analogs & derivatives , Positron-Emission Tomography/methods , Receptors, Histamine H1/metabolism , Administration, Oral , Adult , Antidepressive Agents/administration & dosage , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Area Under Curve , Brain/metabolism , Chromatography, Liquid , Double-Blind Method , Doxepin , Fluvoxamine/administration & dosage , Fluvoxamine/pharmacokinetics , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , Male , Mianserin/administration & dosage , Mianserin/pharmacokinetics , Mianserin/pharmacology , Mirtazapine , Sleep Stages/drug effects , Tandem Mass Spectrometry , Young AdultABSTRACT
The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double-blind, placebo-controlled, three-way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on-the-road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.
Subject(s)
Antidepressive Agents/adverse effects , Automobile Driving , Cognition/drug effects , Piperazines/adverse effects , Psychomotor Performance/drug effects , Sulfides/adverse effects , Adult , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Mianserin/adverse effects , Mianserin/analogs & derivatives , Mianserin/pharmacokinetics , Mianserin/pharmacology , Mirtazapine , Piperazines/pharmacokinetics , Piperazines/pharmacology , Sulfides/pharmacokinetics , Sulfides/pharmacology , VortioxetineABSTRACT
In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrollment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and ≥ 2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products.
Subject(s)
Antidepressive Agents, Tricyclic/administration & dosage , Antidepressive Agents, Tricyclic/pharmacokinetics , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Mianserin/analogs & derivatives , Cross-Over Studies , Female , Genotype , Healthy Volunteers , Humans , Male , Mianserin/administration & dosage , Mianserin/pharmacokinetics , Mirtazapine , Pharmacogenetics/methods , Sample Size , Therapeutic EquivalencyABSTRACT
Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.
Subject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Cytochrome P-450 CYP2D6/genetics , Depressive Disorder, Major/drug therapy , Mianserin/analogs & derivatives , Adult , Age Factors , Aged , Antidepressive Agents, Tricyclic/chemistry , Antidepressive Agents, Tricyclic/pharmacokinetics , Cytochrome P-450 CYP1A2/metabolism , Depressive Disorder, Major/physiopathology , Drug Monitoring/methods , Female , Genotype , Humans , Male , Mianserin/chemistry , Mianserin/pharmacokinetics , Mianserin/therapeutic use , Middle Aged , Mirtazapine , Pharmacogenetics , Psychiatric Status Rating Scales , Sex Factors , Smoking/metabolism , Stereoisomerism , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: An integrated method that provides rates of both parent disappearance and metabolite formation was developed. RESULTS: Buspirone, mirtazapine and verapamil were used as model compounds in developing the method. Incubations were carried out on a robotic platform. Qualitative analysis of metabolites in 30 µM samples was conducted by data-dependent HPLC-MS/MS on a high-resolution instrument. Quantitative analysis of the parent compound and metabolites in 0.5 µM samples was conducted by full-scan MS(2) with product ion extraction using an ion trap mass spectrometer. Data generated for the compounds included half-life and intrinsic clearance of the parent molecule, characterization of metabolites and relative rates of metabolite formation. A correction factor was used to convert MS responses of metabolites in 0.5 µM samples to UV areas in order to compare relative metabolite concentrations. CONCLUSION: The approach allows for the investigation of a set of six compounds simultaneously, with a turnaround time of 1 week or less.
Subject(s)
Chemistry Techniques, Analytical , Drug Evaluation, Preclinical/methods , Pharmacokinetics , Animals , Automation , Biotransformation , Buspirone/analysis , Buspirone/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Dogs , Half-Life , Humans , Mianserin/analogs & derivatives , Mianserin/analysis , Mianserin/pharmacokinetics , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Mirtazapine , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry/methods , Verapamil/analysis , Verapamil/pharmacokineticsABSTRACT
OBJECTIVE: In the framework of a case report on a patient suffering from major depression and inflammatory bowel disease we address the pharmacotherapeutical options in case of subtherapeutic mirtazapine levels. METHODS: We applied therapeutic drug monitoring (TDM) and cytochrome P450 2D6 genotyping, and switched to an orodispersible tablet. RESULTS AND CONCLUSION: Thus, mirtazapine plasma levels could be raised and clinical improvement of the depressive symptoms was achieved.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antidepressive Agents, Tricyclic/therapeutic use , Colitis, Ulcerative/diagnosis , Depressive Disorder, Major/drug therapy , Mianserin/analogs & derivatives , Alleles , Anti-Inflammatory Agents/adverse effects , Antidepressive Agents, Tricyclic/adverse effects , Antidepressive Agents, Tricyclic/pharmacokinetics , Colitis, Ulcerative/blood , Colitis, Ulcerative/psychology , Combined Modality Therapy , Cytochrome P-450 CYP2D6/genetics , Depressive Disorder, Major/blood , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/psychology , Dose-Response Relationship, Drug , Genetic Carrier Screening , Humans , Liver/enzymology , Male , Mesalamine/adverse effects , Mesalamine/therapeutic use , Metabolic Clearance Rate/genetics , Mianserin/adverse effects , Mianserin/pharmacokinetics , Mianserin/therapeutic use , Middle Aged , Mirtazapine , Patient AdmissionABSTRACT
OBJECTIVE: Mirtazapine is a tetracyclic antidepressant which works relating to noradrenergic and elective serotoninergic receptors. The aim of this study was to assess the pharmacokinetic properties and bioequivalence of a newly developed tablet formulation of mirtazapine with those of an established branded formulation in healthy Chinese male volunteers. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-way crossover study was conducted in healthy Chinese volunteers under fasting conditions with a washout of 14 days between the study periods. A sensitive and credible high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to determine mirtazapine in human plasma. RESULTS: The main PK parameters of the mirtazapine test and reference tables were as follows: mean (SD) C(max), 58.715 (23.89) and 58.255 (22.34) ng/ml; AUC(0-t), 591.406 (186.79) and 596.339 (201.25) ng × h/ml; AUC(0-∞), 627.03 (201.39) and 631.521 (227.32) ng × h/ml; t(1/2), 18.941 (4.79) and 18.285 (3.91) h; t(max) 1.417 (0.61) and 1.424 (0.75) h. The 90% CI for logtransformed ratios of C(max) (88.8 - 112.4%), AUC(0-t) (93.9 - 104.9%) and AUC(0-∞) (94.5 - 105.3%) for the test and reference formulations respectively, meeting the predetermined criteria for bioequivalence. CONCLUSIONS: Both treatments exhibited similar tolerability and safety. The test product is therefore bioequivalent to the reference product with respect to the rate and extent of mirtazapine pharmacokinetics.
Subject(s)
Antidepressive Agents, Tricyclic/pharmacokinetics , Mianserin/analogs & derivatives , Administration, Oral , Adult , Antidepressive Agents, Tricyclic/adverse effects , Antidepressive Agents, Tricyclic/chemistry , Chemistry, Pharmaceutical , Cross-Over Studies , Humans , Male , Mianserin/adverse effects , Mianserin/chemistry , Mianserin/pharmacokinetics , Mirtazapine , Tablets , Therapeutic Equivalency , Young AdultABSTRACT
In the present study a simple, fast, sensitive and robust method to quantify mirtazapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by a simple protein precipitation with methanol and were analyzed by high-performance liquid chromatography coupled to an electrospray tandem triple quadrupole mass spectrometer (HPLC-ESI-MS/MS). Chromatography was performed isocratically on a C(18), 5 µm analytical column and the run time was 1.8 min. The lower limit of quantitation was 0.5 ng/mL and a linear calibration curve over the range 0.5-150 ng/mL was obtained, showing acceptable accuracy and precision. This analytical method was applied in a relative bioavailability study in order to compare a test mirtazapine 30 mg single-dose formulation vs a reference formulation in 31 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a 14 day washout period. Since the 90% confidence interval for C(max) , AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration and ANVISA (Brazilian Health Surveillance Agency), it was concluded that mirtazapine 30 mg/dose is bioequivalent to the reference formulation, according to both the rate and extent of absorption.
Subject(s)
Chromatography, High Pressure Liquid/methods , Mianserin/analogs & derivatives , Tandem Mass Spectrometry/methods , Adult , Area Under Curve , Biological Availability , Cross-Over Studies , Dibenzothiazepines/blood , Drug Stability , Female , Humans , Linear Models , Male , Mianserin/blood , Mianserin/chemistry , Mianserin/pharmacokinetics , Middle Aged , Mirtazapine , Quetiapine Fumarate , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Mirtazapine (MRT) is a human antidepressant drug mainly metabolised by the cytochrome P450 enzyme system to 8-OH mirtazapine (8-OH) and dimetilmirtazapine (DMR). The drug is usually administered to dogs with anorexia according to doses extrapolated from humans, although it could also have applications as an antidepressant and analgesic in this species. The aim of this study was to assess the pharmacokinetics of MRT and its metabolites, DMT and 8-OH. Six healthy male Beagle dogs were administered MRT orally (20 mg/dog) and plasma MRT and metabolite concentrations were evaluated by high performance liquid chromatography with fluorescence detection. The pharmacokinetic profiles of MRT and DMR were similar (detected from 0.25 up to 10 h), while 8-OH (detected from 0.50 up to 10 h) attained the highest concentrations. The mean half-life of MRT was 6.17 h with a clearance of 1193 mL/h/kg. The study showed that MRT has a different pharmacokinetic profile in the dog compared to other species.