Pharmacobezoar Associated Prolonged Clinical Course in a Patient with Immediate Release Quetiapine Overdose.

INTRODUCTION: Quetiapine is available in both immediate-release (IR) and extended-release (XR) formulations. Quetiapine XR overdose is known to cause delayed increase in serum quetiapine concentrations. However, it is not certain whether quetiapine IR overdose would similarly cause a delayed increase in serum quetiapine concentrations. CASE REPORT: A 57-year-old woman with depression who was taking half a tablet of 25 mg quetiapine IR daily was transported to our emergency department with a complaint of disturbance of consciousness 12 h after a quetiapine IR overdose. On arrival, her initial vital signs were heart rate of 116 beats per minute, blood pressure of 77/43 mm Hg, and oxygen saturation of 91% under 10 L oxygen administration. Whole body plain computed tomography showed a large amount of gastric hyperdense content suggesting pharmacobezoar with a volume of 71.2 ml. After treatment with respiratory and circulatory support, gastric lavage was performed. Her disturbance of consciousness persisted until day 5, and she was extubated on day 7. The serum concentrations of quetiapine were 2690 ng/mL at 12 h after overdose, 5940 ng/mL at 40 h, and 350 ng/mL at 124 h after overdose. Serum concentrations of other co-ingestions were all below lethal levels. CONCLUSION: A massive quetiapine IR overdose with pharmacobezoars can cause a delayed increase in serum quetiapine concentrations.

Detecting the therapeutic drugs in blood samples through PDMS-printed paper spray mass spectrometry.

In this paper, paper microfluidic channel fabricated by directly screen-printing of polydimethylsiloxane (PDMS) is proposed for paper spray mass spectrometry analysis of therapeutic drugs in the blood samples. Compared with traditional paper spray, PDMS-printed paper spray (PP-PS) allows fluid to flow to the tip of paper with less sample loss which significantly improved the signal intensity of target compounds in blood samples. As paper can reduce the matrix effect, PP-PS also has a greater advantage than electro-spray Ionization (ESI) when directly analyzing complex biological sample in terms of the detection efficiency. Linearity and limits of detection (LOD) were evaluated for five psychotropic drugs: olanzapine, quetiapine, 9-hydroxyrisperidone, clozapine, risperidone. As a result, PP-PS improved the signal intensity of the psychotropic drugs at a concentration of 250 ng/ml in blood samples by a factor of 2-5 times and lowered the relative standard deviation (RSD) by a factor of 2-5.6 times compared with traditional paper spray. And PP-PS also improved signal intensity by a factor of 9-33 times compared with ESI. Quantitative experiments of PP-PS mass spectrometry indicated that the linear range was 5-500 ng/ml and the LOD were improved by a factor of 5-71 times for all these drugs compared with traditional paper spray. In addition, PP-PS was applied to the home-made miniaturized mass spectrometer and the precursor ions of all five psychotropic drugs (250 ng/ml) in the mass spectrometry results were obtained as well. These could prove that PP-PS has the potential to analyze complex biological samples in application on the miniaturized mass spectrometer which can be used outside the laboratory.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

PURPOSE/BACKGROUND: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). METHODS/PROCEDURES: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. FINDINGS/RESULTS: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. IMPLICATIONS/CONCLUSIONS: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Infection is associated with elevated serum concentrations of antipsychotic drugs.

We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.

Identification and Quantification of Antipsychotics in Blood Samples by LC-MS-MS: Case Reports and Data from Three Years of Routine Analysis.

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.

Approach to Evaluating QT Prolongation of Quetiapine Fumarate in Late Stage of Clinical Development Using Concentration-QTc Modeling and Simulation in Japanese Patients With Bipolar Disorder.

PURPOSE: Quetiapine has been reported to prolong the QT interval, and has been used as a positive control in thorough QT studies. The objective of the present study was to evaluate, in the late stages of clinical development, the QT-prolongation effects of the extended-release (XR) formulation of quetiapine at the approved dose in Japanese patients with bipolar disorder, using concentration-QT modeling and simulation. METHODS: Plasma concentrations of quetiapine and 4 of its metabolites (M1, M2, M4, and M5), and the QT interval corrected using the Fridericia formula (QTcF), were used for the concentration-QT analysis. Data from intensive electrocardiogram monitoring at predose and at 4, 6, 10, and 24 h after the administration of the last dose were pooled from a Phase I trial (6949-CL-0006) and from sparse sampling in late-stage clinical trials (6949-CL-0005, -0021, -0022, and -0023) in Japanese patients (N = 505). The upper limit of 1-sided 95% confidence interval (CI) of the changes from baseline in QTcF (ΔQTcF) at the geometric mean Cmax of a therapeutic dose of 300 mg once daily was predicted using a linear mixed-effects model, with the intercept as a random effect specifying a subject effect. FINDINGS: For quetiapine and M2, but not M1, M4, or M5, positive slopes were observed between ΔQTcF and concentration. The predicted upper limits of the 1-sided 95% CIs did not exceed the regulatory threshold of 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose of quetiapine XR. IMPLICATIONS: In this pooled data analysis of the QT-prolongation effects of the quetiapine XR, positive relationships between ΔQTcF and quetiapine and M2 concentrations were observed. However, the predicted upper limits of the 1-sided 95% CIs did not exceed 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose. ClinicalTrials.gov identifiers: NCT01725282, NCT01919008, NCT01725308, NCT01737268, and NCT02362412.

Semi-Mechanistic Pharmacokinetic Modeling of Lipid Core Nanocapsules: Understanding Quetiapine Plasma and Brain Disposition in a Neurodevelopmental Animal Model of Schizophrenia.

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous bolus dose of FQ or QLNC to naive and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bidirectional drug transport across the blood-brain barrier (CLin and CLout). SCZ-like rats' significant decrease in brain exposure with FQ (decrease in CLin) was reverted by QLNC, showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LNC for brain delivery. SIGNIFICANCE STATEMENT: A population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of the drug's brain distribution following administration of both free drug in solution or as nanoformulation to naive and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment-limited response rates.

Population Pharmacokinetics Analysis of Quetiapine Extended-release Formulation in Japanese Patients with Bipolar Depression.

PURPOSE: The objectives of this study were to explore covariates of plasma quetiapine concentrations after oral administration of quetiapine extended-release formulation (XR), and to examine the exposure-response relationship in Japanese patients with bipolar depression, using population pharmacokinetics (PopPK) modeling. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study of quetiapine XR in patients with bipolar depression, plasma for the measurement of quetiapine concentration was collected at weeks 2, 4, 8, 12, 20, 28, and 52 during oral administration of 150 or 300 mg once daily of quetiapine XR before bedtime. A PopPK model of quetiapine XR was developed using nonlinear mixed-effects modeling with first-order conditional estimation with interactions. The exposure-response relationship was examined using post-hoc exposures. The post-hoc AUC estimate was plotted against the change in the Montgomery-Åsberg Depression Rating Scale (ΔMADRS) total score from baseline to 8 weeks following once-daily doses at 300 mg. FINDINGS: The final PopPK analysis dataset contained 322 patients and 1162 observations (cutoff data at week 28; cutoff date, February 2016). The plasma quetiapine concentration-time profile in patients with bipolar depression after oral administration of quetiapine XR was represented well using a 1-compartment with first-order absorption model. Covariate analysis led to the selection of γ-glutamyl transpeptidase on apparent oral clearance and body weight on apparent volume of distribution as covariates. The final population mean values of apparent oral clearance and apparent volume of distribution were 87.7 L/h and 277 L, respectively, and the interindividual %CVs were 32.6% and 75.0%, respectively. IMPLICATIONS: The effects of covariates on PK parameters were not large compared with the interindividual variability. In addition, there was no clear relationship between the AUC and ΔMADRS. ClinicalTrials.gov identifier: NCT01725308.

Characteristics of quetiapine and 7-hydroxyquetiapine in hair roots and blood after a single dose of quetiapine.

This study investigated the kinetics of quetiapine and its metabolite 7-hydroxyquetiapine in guinea pig blood and hair roots during the whole time course of absorption and elimination after intragastric administration of three dosages (25 mg/kg, 50 mg/kg, 100 mg/kg). The mean maximum concentration (Cmax) values of quetiapine in the blood of the low-, medium- and high-dose groups were 334.4, 849.0, and 2751.1 ng/mL, respectively, and those of 7-hydroxyquetiapine were 75.6, 175.5, and 173.7 ng/mL, respectively. The corresponding mean Cmax values of quetiapine in hair roots were 2.0, 5.9, and 14.7 ng/mg, and those of 7-hydroxyquetiapine were 1.0, 1.8, and 6.4 ng/mg. The mean half-lives of quetiapine at the three dosages in blood were 3.8 h, 5.0 h, and 6.0 h, and those in hair roots were 48.2 h, 41.5 h, and 162.3 h; for 7-hydroxyquetiapine, the values were 2.9 h, 4.1 h, and 4.2 h in blood and 77.1 h, 103.6 h, and 385.9 h in hair roots. The levels of quetiapine in blood and hair roots were higher than those of 7-hydroxyquetiapine, and there were significant positive correlations (p<0.05) between the concentrations of quetiapine and 7-hydroxyquetiapine in hair roots and the respective doses within 24 h and 48 h. Quetiapine and 7-hydroxyquetiapine could still be detected in some guinea pigs even after 28 days, which means that drugs remain in the hair roots longer than in the blood. This finding shows that hair roots could be a good alternative or supplemental matrix to common biological samples such as blood and urine, as hair roots substantially extend the detection window from days to months. Moreover, quetiapine and 7-hydroxyquetiapine were detected within 15min after administration in hair roots, which also suggests that the drug enters the hair roots quickly. Therefore, hair root analysis may be a good choice to detect acute poisoning and single-dose administration if other matrices are unavailable or to provide complementary information for other matrices.

Quetiapine dose optimisation during gestation: a pharmacokinetic modelling study.

OBJECTIVES: The second-generation antipsychotic quetiapine has been demonstrated to undergo gestation-related changes in pharmacokinetics. This study applied pharmacokinetic modelling principles to investigate the mechanism of these changes and to propose new dosing strategies to counteract these changes. METHODS: A pharmacokinetic modelling approach was implemented using virtual population groups. Changes in quetiapine trough plasma concentration during gestation were quantified across all trimesters, and dose adjustment strategies were applied to counteract these changes by targeting a therapeutic range of 50-500 ng/ml throughout gestation. KEY FINDINGS: The application of the model during gestation predicted a decrease in trough concentration. A maximum decrease of 58% was predicted during trimester 2, and being associated with a statistically significant decrease in oral clearance at gestation week 25, 204 l/h ± 100.8 l/h compared with non-pregnant subjects, 121.9 l/h ± 51.8 l/h. A dosing optimisation strategy identified that dose increases to 500-700 mg twice daily would result in 32-55% of subjects possessing trough concentration in excess of 50 ng/ml. CONCLUSIONS: Quetiapine doses in pregnancy should be increased to 500-700 mg twice daily to counteract a concomitant increase in metabolic clearance, increase in volume of distribution and decrease in plasma protein binding.

Quality by design applied to olanzapine and quetiapine LC-MS/MS bioanalysis.

One major challenge in quantifying drugs in biological matrices is to manage interfering compounds. A technique such liquid chromatography coupled to mass spectrometry in tandem (LC-MS/MS) is especially suitable for this application due to its high sensitivity and selectivity in detecting low concentrations of analytes in a complex system. Due to the complexity of LC-MS/MS systems, a number of experimental parameters must be optimized to provide an adequate separation and detection of the analyte. In the present work, a design of experiments approach was developed to optimize an LC-MS/MS-based bioanalytical method to extract olanzapine (OLZ) and quetiapine (QTP) from human plasma. Three steps for the optimization process were conducted: central composite face-centered design to optimize chromatographic parameters (Step 1), ionization in mass spectrometry (Step 2) and a full 32 factorial design to optimize analyte extraction conditions (Step 3). After the optimization process, resolutions and QTP and OLZ retention time (2.3 and 4, respectively) were optimum with pH of 4.7 and 85.5% of acetonitrile for the chromatographic step. Mass spectrometry optimization step provided an increase of (±50%) in the average peak area with high signal-to-noise relationship for the analytes studied. The proposed extraction method was 70% more efficient than the initial method for all drugs analyzed.

Severe quetiapine voluntary overdose successfully treated with a new hemoperfusion sorbent.

Quetiapine overdose, although rare, is mainly linked with tachycardia, QTc-interval prolongation, somnolence, coma, hyperglycemia, and eventually hepatotoxicity and myocarditis. Extracorporeal techniques for quetiapine removal might be helpful, but only a few cases are reported in the literature. We here describe the case of a 27-year-old healthy woman, admitted to our Intensive Care Unit after voluntary quetiapine intake and successfully treated with CytoSorb hemoperfusion in combination with continuous renal replacement therapy (CRRT), in order to accelerate quetiapine elimination. This is the first published experience about the potential application of hemoadsorption therapies, as CytoSorb sorbent, in large overdoses of quetiapine and this approach might be feasible to rapidly remove the substance from blood, stabilizing the patient condition.

Impact of Quetiapine Therapy on QTc Prolongation in Critically Ill Patients.

BACKGROUND: Quetiapine is an atypical antipsychotic commonly utilized for the management of delirium in critically ill patients. The impact of quetiapine on QTc in the critically ill population is largely unknown. OBJECTIVE: The purpose of this study was to evaluate QTc prolongation following administration of quetiapine for the management of delirium in critically ill patients. METHODS: This was a single-center prospective, observational cohort study. QTc measurements of patients who received at least one dose of quetiapine were compared with a control group receiving melatonin. The primary outcome was mean change in QTc from baseline to maximum serum drug concentration after the first dose of quetiapine. RESULTS: No significant change in QTc was observed from baseline to post-quetiapine administration, with a mean change in QTc of 2.7 ms (438.4 ± 43.2 ms vs 441.1 ± 36.4 ms; P = 0.50). When comparing mean change in QTc between the quetiapine group and melatonin group, the difference was not significant (2.7 ± 37.8 ms vs -0.18 ± 32.0 ms, P = 0.73). Conclusion and Relevance: This study represents one of the first prospective studies evaluating the impact of quetiapine on QTc. The results of this study demonstrate a nonsignificant statistical and clinical change in the QTc following quetiapine administration in critically ill patients utilizing telemetry measurements. Routine QTc monitoring with formal electrocardiogram(s) following quetiapine administration may not be warranted.

Bioequivalence of two quetiapine extended release tablets in Chinese healthy volunteers under fasting and fed conditions and effects of food on pharmacokinetic profiles.

OBJECTIVE: The objectives of this study were to evaluate the bioequivalence of Quesero extended release (Quesero XR) tablets and Seroquel extended release (Seroquel XR) tablets under fasting and fed conditions and to determine the effect of food on the pharmacokinetic (PK) properties of Quesero XR or Seroquel XR in Chinese healthy volunteers. METHODS: A single-site, randomized, open-label, two-period crossover design with a 10-day washout period was conducted in 20 subjects under the fed and fasting studies. A single oral dose of 200 mg Quesero XR or Seroquel XR was given to the subjects after an overnight fast of 10 hours. Blood samples were taken at scheduled time spots from 0 hour pre dose to 36 hours post dose. Plasma concentrations of quetiapine were measured by a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The PK parameters were calculated by non-compartment analysis using Phoenix WinNonlin software. RESULTS: On both conditions, no significant differences were found among the main PK parameters of the two preparations by analysis of variance (P>0.05); the Wilcoxon test of maximum peak plasma concentration (Tmax) showed no significant differences (P>0.05); the 90% confidence limit (CL) of lnCmax, lnAUC0→36, and lnAUC0→∞ fell within the acceptable range of 80%-125%. As compared with the fasting state, the Tmax was advanced and the mean maximum plasma concentration (Cmax), AUC0→36, and AUC0→∞ were also increased in the fed state; the geometric mean ratio and 90% CI of the main PK parameters fell outside the range of the CIs; analysis of variance showed significant differences in the other PK parameters except for apparent total clearance after oral administration (clearance rate; P<0.05). CONCLUSION: The two formulations of Quesero XR and Seroquel XR are bioequivalent under both fasting and fed conditions, and food may affect the PK profiles by increasing the rate and extent of absorption of Quesero XR or Seroquel XR in Chinese healthy volunteers.

Butyl Methacrylate-Co-Ethylene Glycol Dimethacrylate Monolith for Online in-Tube SPME-UHPLC-MS/MS to Determine Chlopromazine, Clozapine, Quetiapine, Olanzapine, and Their Metabolites in Plasma Samples.

This manuscript describes a sensitive, selective, and online in-tube solid-phase microextraction coupled with an ultrahigh performance liquid chromatography-tandem mass spectrometry (in-tube SPME-UHPLC-MS/MS) method to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples from schizophrenic patients. Organic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolith was synthesized on the internal surface of a fused silica capillary (covalent bonds) for in-tube SPME. Analyte extraction and analysis was conducted by connecting the monolithic capillary to an UHPLC-MS/MS system. The monolith was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectrometry (FTIR). The developed method presented adequate linearity for all the target antipsychotics: R² was higher than 0.9975, lack-of-fit ranged from 0.115 to 0.955, precision had variation coefficients lower than 14.2%, and accuracy had relative standard error values ranging from -13.5% to 14.6%, with the exception of the lower limit of quantification (LLOQ). The LLOQ values in plasma samples were 10 ng mL-1 for all analytes. The developed method was successfully applied to determine antipsychotics and their metabolites in plasma samples from schizophrenic patients.

A rapid LC-MS/MS method for simultaneous determination of quetiapine and duloxetine in rat plasma and its application to pharmacokinetic interaction study.

Combinations of new antidepressants like duloxetine and second-generation antipsychotics like quetiapine are used in clinical treatment of major depressive disorder, as well as in forensic toxicology scenarios. The drug-drug interaction (DDI) between quetiapine and duloxetine is worthy of attention to avoid unnecessary adverse effects. However, no pharmacokinetic DDI studies of quetiapine and duloxetine have been reported. In the present study, a rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of quetiapine and duloxetine in rat plasma. A one-step protein precipitation with acetonitrile was applied for sample preparation. The analytes were eluted on an Eclipse XDB-C18 column using the mixture of acetonitrile and 2 mM ammonium formate containing 0.1% formic acid at a gradient elution within 6.0 min. Quantification was performed in multiple-reaction-monitoring mode with the ion transitions m/z 384.4 â†’ 253.2 for quetiapine, m/z 298.1 â†’ 154.1 for duloxetine and m/z 376.2 â†’ 165.2 for IS (haloperidol), respectively. Good linearity was obtained in the range of 0.50-100 ng/mL for quetiapine (r2 = 0.9972) and 1.00-200 ng/mL for duloxetine (r2 = 0.9982) using 50 µL of rat plasma, respectively. The method was fully validated with accuracy, precision, matrix effects, recovery and stability. The validated data have met the acceptance criteria in FDA guideline. The method was applied to a pharmacokinetic interaction study and the results indicated that quetiapine had significant effect on the enhanced plasma exposure of duloxetine in rats under combination use. This study could be readily applied in therapeutic drug monitoring of major depressive disorder patients receiving such drug combinations.

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction.

Kratom is a plant with dose-dependent mixed stimulant and opioid properties whose pharmacologic characteristics and social impact continue to be described. The main active isolate of kratom is mitragynine, an indole-containing alkaloid with opioid-like effects. Kratom toxicity and kratom-associated fatalities have been described, including those in association with additional drugs. In this paper we describe the case of a 27-year-old man who was found deceased with a toxic blood concentration of quetiapine in conjunction with the qualitative presence of mitragynine. Investigative and autopsy findings suggested perimortem hyperthermia and seizure-like activity. Kratom toxicity and kratom-associated fatalities are being increasingly reported. Experiments with kratom extracts have shown inhibitory effects upon hepatic CYP enzymes, leading to previous speculation of the potential for clinically significant interactions between kratom and a wide array of medications. Herein is described a fatal case of quetiapine toxicity complicated by mitragynine use. The potential ability of mitragynine to alter the pharmacokinetics of a prescription medication via inhibition of its hepatic metabolism is discussed.

A definite measure of occupancy exposures, seeking with non-radiolabeled in vivo 5-HT2A receptor occupancy and in vitro free fractions.

Unbound drug concentration in the brain would be the true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate the clinical dose projection. With the application of mass spectrometry, the current work proposes a definite measure of test drug exposures at serotonin-2A occupancy. The 5-HT2A occupancy of antagonist in the rat brain has determined with non-radiolabeled tracer MDL-100,907 at an optimized dose (3 µg/kg) and treatment time (30 min). Equilibrium dialysis method determines the in vitro free fraction of the test antagonist in untreated rat brain homogenates and plasma. Drug-free fractions derived the unbound concentration (EC50) in plasma and brain at test doses. The corresponding binding affinities (Ki) correlated with the unbound concentrations. Except for quetiapine, the ED50 values in the dose-occupancy curves of antagonists are close and ranged from 1 to 3 mg/kg. The test drug quetiapine, eplivanserin, and clozapine showed high free fractions in plasma, but for ketanserin and olanzapine, the brain free fraction was higher. The correlation between the unbound EC50 of the antagonists and corresponding Ki values was good (r2=0.828). The improved EC50 accuracy with unbound concentrations was 10-250 folds in plasma and 10-170 folds in the brain. Further, the free fractions (fu, plasma/fu, brain) of test drugs had shown a correlation of ∼83% with brain permeability (Ctotal brain/Ctotal plasma), a limiting factor. Thus, correlating the occupancy with unbound exposure and pharmacology would result in an accurate measurement of drug potency and optimizes in selecting the clinical dose.