Fetal behavior and gestational serotonin reuptake inhibitor exposure: relationships between behavior, drug dosage, plasma drug level, and a measure of drug bioeffect.

Determination of the relationships between drug dosage, maternal and infant (cord blood) plasma drug concentrations, and serotonin reuptake inhibitor (SRI) bioeffect on offspring neurobehavior is crucial to assessing the effects of gestational SRI exposure. Measurement of maternal and cord blood platelet serotonin (5-HT) provides an index of inhibitory bioeffect at the 5-HT transporter and complements other measures of drug exposure. Three groups of mother-infant pairs were evaluated: (1) mothers with depression untreated with SRIs (DEP, n = 17), (2) mothers treated for depression with SRIs (DEP + SRI, n = 17), and (3) mothers who were not depressed and untreated (ND, n = 29). Fetal movement was assessed using a standardized ultrasound imaging and rating protocol. Maternal and cord blood platelet 5-HT levels were obtained from all participants. For the SRI + DEP group, maternal and infant plasma drug concentrations and an estimate of third-trimester maternal SRI drug exposure were obtained. As expected, substantially lower median platelet 5-HT levels were observed in the DEP + SRI group than in the non-exposed, combined ND and DEP groups. In non-exposed mothers and infants, platelet 5-HT levels were not affected by the presence of maternal depression. Lower maternal and infant platelet 5-HT levels were associated with more immature fetal movement quality. Although these data are limited by small sample size, the bioeffect index of in vivo platelet 5-HT transporter inhibition appears to provide a valuable approach for elucidating and possibly predicting the effects of gestational SRI exposure on fetal and perinatal neurobehavior.

Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

AIMS: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. METHODS: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. RESULTS: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CONCLUSIONS: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

The Tissue-Specific Eco-Exposome: Differential Pharmaceutical Bioaccumulation and Disposition in Fish among Trophic Positions.

Though bioaccumulation of pharmaceuticals by aquatic organisms continues to receive scientific attention, the internal disposition of these contaminants among different tissue compartments of fish species has been infrequently investigated, particularly among fish at different trophic positions. We tested a human to fish biological read-across hypothesis for contaminant disposition by examining tissue-specific accumulation in three understudied species, longnose gar (Lepisosteus osseus; piscivore), gizzard shad (Dorosoma cepedianum; planktivore/detritivore), and smallmouth buffalo (Ictiobus bubalus; benthivore), from a river influenced by municipal effluent discharge. In addition to surface water, fish plasma, and brain, gill, gonad, liver, and lateral muscle fillet tissues were analyzed via isotope dilution liquid chromatography tandem mass spectrometry. Caffeine and sucralose, two common effluent tracers, were quantitated at low micrograms per liter levels in surface water, while an anticonvulsant, carbamazepine, was observed at levels up to 37 ng/L. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and primary metabolites were detected in at least one tissue of all three species at low micrograms per kilogram concentrations. Within each species, brain and liver of select fish contained the highest levels of SSRIs compared to plasma and other tissues, which is generally consistent with human tissue disposition patterns. However, we observed differential accumulation among specific tissue types and species. For example, mean levels of sertraline in brain and liver tissues were 13.4 µg/kg and 1.5 µg/kg in gizzard shad and 1.3 µg/kg and 7.3 µg/kg in longnose gar, respectively. In contrast, smallmouth buffalo did not consistently accumulate SSRIs to detectable levels. Tissue-specific eco-exposome efforts are necessary to understand mechanisms associated with such marked bioaccumulation and internal dispositional differences among freshwater fish species occupying different trophic positions. Environ Toxicol Chem 2024;43:1894-1902. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Population Pharmacokinetics of Sertraline in Psychiatric and Substance Use Disorders.

This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty-nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first-order conditional estimation method. A one-compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response.

Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine.

Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox-Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child-Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area-under-the-curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0-∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36-2.90), 2.13 (1.43-3.17), and 2.77 (1.82-4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure-response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.

Changes in Sertraline Plasma Concentrations Across Pregnancy and Postpartum.

Major depressive disorder (MDD) is a common disorder in pregnancy. Although sertraline is the most frequently prescribed antidepressant for pregnant people in the United States, limited information about its pharmacokinetics in pregnancy is available. Our objectives were to characterize plasma sertraline concentration to dose (C/D) ratios across pregnancy and postpartum and investigate the effect of pharmacogenetic variability on sertraline elimination. We performed a prospective observational cohort study in people with a singleton pregnancy ≤ 18 weeks gestation and a lifetime diagnosis of MDD at the 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded Obstetrical-Fetal Pharmacology Research Center sites. Subjects (N = 47) were receiving maintenance sertraline therapy and chose to continue it during pregnancy. Blood samples were obtained 24-hours postdose every 4 weeks across pregnancy and twice postpartum for measurement of plasma concentrations of sertraline and desmethylsertraline. Overall mean sertraline C/D ratios were decreased at study onset and remained consistently low until after delivery. During the last 4 weeks of pregnancy the mean sertraline C/D ratio (95% confidence interval (CI)), 0.25 (95% CI, 0.19, 0.3) ng/mL/dose (mg/day), was smaller than the mean ratio at ≥ 8 weeks after delivery, 0.32 (95% CI, 0.27, 0.37) ng/mL/dose (mg/day), a 22% difference. Mean sertraline/desmethylsertraline ratios were highest after birth, which confirmed increased sertraline elimination during pregnancy. Sertraline C/D ratios in participants with functional CYP2C19 activity did not change significantly during pregnancy, whereas ratios in participants with poor or intermediate CYP2C19 activity decreased by 51%. Exploratory pharmacogenomic analysis indicated that pregnant people with poor or intermediate CYP2C19 activity are at risk for subtherapeutic sertraline concentrations during pregnancy.

Effects of CYP2D6*4 polymorphism on the steady-state concentration of paroxetine in patients diagnosed with depressive episode and comorbid alcohol use disorder.

INTRODUCTION: Selective serotonin reuptake inhibitors have a common and increasing use for the treatment of patients diagnosed with depressive disorders. Some of them do not respond adequately to therapy, and numerous previous studies have indicated an increased risk of type A adverse drug reactions. OBJECTIVE: The objective of our study was to evaluate the effect of 1846G>A polymorphism of CYP2D6 on the concentration/dose ratio of paroxetine. MATERIAL AND METHODS: The study enrolled 267 patients with depressive episode (average age, 40.3 ± 14.3 years). Therapy included paroxetine in an average daily dose of 25.1 ± 9.5 mg per day. The efficacy and safety rates of treatment were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Therapeutic drug monitoring has been performed using high-performance liquid chromatography mass spectrometry (HPLC-MS/MS). RESULTS: Our study revealed the statistically significant results in terms of treatment efficacy (Hamilton Depression Rating Scale scores): (GG) 2.0 [1.0; 3.0] and (GA) 4.0 [2.0; 5.0], p < 0.001; meanwhile, no statistically significant results were obtained for the safety profile (Udvalg for Kliniske Undersogelser (UKU) Scale scores): (GG) 3.0 [2.0; 3.0] and (GA) 3.0 [3.0; 4.0], p = 0.056. We revealed the statistically significant results for the concentration/dose ratio of paroxetine in patients with different genotypes: (GG) 2.803 [2.154; 4.098] and (GA) 5.098 [3.560; 7.241], p < 0.001. CONCLUSION: The effect of CYP2D6*4 genetic polymorphism on the efficacy profile of paroxetine was demonstrated in a group of 267 patients with depressive disorder.

Neurochemical and behavioral effects of fluoxetine on midazolam induce dependence in an animal model of addiction.

In the present study we have monitored effects of repeated coadministration of fluoxetine with midazolam; a benzodiazepine (CNS depressant). It is the primary drug of choice for procedural sedation, preoperative sedation, and in emergency departments. Repeated administration of this drug is reported to have abuse potential and may cause this by increasing dopaminergic neurotransmission. Since an important role of serotonin is there in the pathophysiology of anxiety and addiction, administration of midazolam may involve altered 5-HT metabolism as well. Present study was designed to monitor effects of repeated administration of fluoxetine with midazolam. Effects of fluoxetine and midazolam coadministration were monitored on motor activities in familiar and novel environments, hot plate test, forced swim test, conditioned place preference test and levels of dopamine, 5-HT and their metabolites. Both midazolam (2.5mg/kg) and fluoxetine (1mg/kg) were administered orally for 12 days. Conditioned place preference test was performed on day 13. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study show attenuation of midazolam-induced reinforcement upon repeated co-administration of fluoxetine. These could be implicated to increased therapeutic utility of midazolam and related benzodiazepines.

Factors associated with fluoxetine and norfluoxetine plasma concentrations and clinical response in Mexican patients with mental disorders.

Over the last few years, fluoxetine has been one of the most prescribed medications for the treatment of diverse psychiatric conditions in Mexico. Fluoxetine therapeutic effect is consequence of the joint action of the parent drug and its active metabolite, norfluoxetine. However, the clinical efficacy of fluoxetine, can be affected due to diverse factors, such as drug-drug interactions and the large interindividual variability in the pharmacokinetics of this drug. The aim of this study was to determine the factors associated with variability in plasma concentrations of fluoxetine and norfluoxetine and its association with the therapeutic response. Fluoxetine and norfluoxetine plasma concentrations were quantified by liquid chromatography in 81 Mexican patients with mental disorders; 25% of the patients had no medication adherence and 40% were below the reference range of fluoxetine plus norfluoxetine plasma concentrations. The results showed that concentrations can be affected by fluoxetine metabolism caused by CYP2D6 phenotype and the concomitant administration of olanzapine. Furthermore, CYP3A5 and CYP2C19 phenotype were associated with lower anxiety and depression control during treatment with fluoxetine. This study can be a starting point to elucidate the causes of fluoxetine variable response in Mexican patients with mental disorders, as well as to detect and support medication adherence.

The Impact of Serotonin Transporter Binding Affinity on the Risk of Bleeding Related to Antidepressants.

PURPOSE/BACKGROUND: The alleged primary mechanism underlying bleeding events associated with antidepressants is inhibition of serotonin uptake in platelets resulting in reduced platelet aggregability and activity, and prolonged bleeding time. There is some evidence that a substance's degree of serotonin reuptake inhibition in terms of its binding affinity to the serotonin transporter (SERT) affects the magnitude of bleeding risk increase. METHODS/PROCEDURE: To test this hypothesis, we performed data mining in the worldwide largest pharmacovigilance database (VigiBase) and conducted pharmacodynamically informed quantitative signal detection. Reporting odds ratios related to the standardized Medical Dictionary of Regulatory Activities query term "haemorrhages" and 24 antidepressants were calculated, and SERT binding affinities (pKi) were obtained and correlated (Pearson correlation). FINDINGS/RESULTS: A strong and statistically significant correlation between substance-related reporting odds ratios and SERT binding affinities was found (r = 0.63; 95% confidence interval, 0.30-0.82; P = 0.00097). IMPLICATIONS/CONCLUSIONS: Our findings strengthen the hypothesis that inhibition of serotonin uptake contributes to the antidepressant-related bleeding risk and suggest an association between the degree of the SERT binding affinity and the bleeding risk. This supports the preferential use of antidepressants with low or no SERT binding affinity in depressed patients at risk of bleeding.

Pharmacokinetics, Tolerability and Pharmacogenetics of DA-8031 After Multiple Ascending Doses in Healthy Male Subjects.

PURPOSE: DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031. SUBJECTS AND METHODS: A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMETTM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG). RESULTS: The plasma DA-8031 concentration reached the maximum concentration (Cmax) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild. CONCLUSION: After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.

Prediction of Fluoxetine and Norfluoxetine Pharmacokinetic Profiles Using Physiologically Based Pharmacokinetic Modeling.

Fluoxetine is a selective serotonin reuptake inhibitor that is metabolized to norfluoxetine by cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A4. A physiologically based pharmacokinetic model for fluoxetine and norfluoxetine metabolism was developed to predict and investigate changes in concentration-time profiles according to fluoxetine dosage in the Korean population. The model was developed based on the Certara repository model and information gleaned from the literature. Digitally extracted clinical study data were used to develop and verify the model. Simulations for plasma concentrations of fluoxetine and norfluoxetine after a single dose of 60 or 80 mg fluoxetine were made based on 1000 virtual healthy Korean individuals using the SimCYP version 19 simulator. The mean ratios (simulated/observed) after a single administration of 80 mg fluoxetine for maximum plasma concentration, area under the plasma concentration-time curve, and apparent clearance were 1.12, 1.08, and 0.93 for fluoxetine; the ratios of maximum plasma concentration and area under the plasma concentration-time curve were 1.08 and 1.08, respectively, for norfluoxetine, indicating that the simulated concentration-time profiles of fluoxetine and norfluoxetine fitted the observed profiles well. The developed model was used to predict plasma fluoxetine and norfluoxetine concentration-time profiles after repeated administrations of fluoxetine in Korean volunteers. This physiologically based pharmacokinetic model could provide basic understanding of the pharmacokinetic profiles of fluoxetine and its metabolite under various situations.

The gut microbiome influences the bioavailability of olanzapine in rats.

BACKGROUND: The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. METHODS: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. FINDINGS: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. INTERPRETATION: Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. FUNDING: This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).

Pharmacokinetics and Safety of Dapoxetine Hydrochloride in Healthy Chinese Men: Impact of Dose and High-Fat Meal.

Dapoxetine is the first oral medication specifically developed for the on-demand treatment of premature ejaculation. The pharmacokinetics and safety of 30 mg (n = 40) and 60 mg (n = 38) dapoxetine in healthy Chinese under fasted and fed states were assessed in 2 studies. Both studies are random, single-center, 2-period, open-label, 2-way crossover designs. Plasma concentration of dapoxetine was determined by high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated using noncompartmental analysis. Dapoxetine was quickly absorbed and reached maximum concentration 1 to 3 hours after oral administration. Elimination was biphasic, and the plasma concentration decreased to 3% to 7% of maximum concentration by 24 hours while half-life was 15 to 18 hours. Meantime, high-fat meals slightly increased its exposure. Both doses of dapoxetine were well tolerated. The adverse events in the high-dose group under fasted and fed states were 37.9% and 19.0%, respectively.

Bioequivalence Analysis of 2 Dapoxetine Hydrochloride Formulations in Healthy Chinese Male Volunteers Under Fed and Fasting Conditions: A Randomized, Open-Label, 2-Sequence, 2-Period, 2-Way Crossover Study.

This study assessed whether the reference and test formulations of dapoxetine hydrochloride were bioequivalent under fed and fasting conditions postadministration of a single dose as well as evaluated the safety profile of these 2 formulations. This study was a randomized, single-center, 2-period, open-label, 2-way crossover design study with a washout period of 7 days between each period. The study included 80 subjects, 40 under fed and 40 under fasting conditions. During each study period, the subjects were administered a single oral dose of either the reference or the test formulation, followed by collection of plasma samples 70 hours postdose. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was performed to determine the concentrations of dapoxetine in plasma samples along with the calculation of Cmax , AUC0-t, and AUC0-inf . In addition, adverse events were monitored to determine the safety of these formulations. The geometric mean ratio (90%CI) for the reference and test formulations was 86% to 100%, 89% to 103%, and 89% to 103% under fasting conditions and 92% to 107%, 91% to 100%, and 92% to 101% under fed conditions for Cmax , AUC0-t , and AUC0-inf , respectively. The 90%CIs for the test/reference ratio for AUC and Cmax were within the acceptable limits of bioequivalence, thus demonstrating bioequivalence for these 2 dapoxetine hydrochloride formulations.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis.

PURPOSE: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. METHODS: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). RESULTS: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). DISCUSSION: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

Escitalopram in Adolescents With Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.

Intravenous vortioxetine to accelerate onset of effect in major depressive disorder: a 7-day randomized, double-blind, placebo-controlled exploratory study.

This 7-day randomized, double-blind, placebo-controlled fixed-dose study (NCT03766867) explored the potential for accelerating the onset of antidepressant efficacy of single-dose intravenous (IV) vortioxetine at oral vortioxetine treatment initiation. Patients (ages 18-65 years) hospitalized per standard-of-care with major depressive disorder, who were currently treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for a major depressive episode [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 30], received one dose of single-blind IV placebo (1-day placebo lead-in period) before being randomly switched to either single-dose IV vortioxetine 25 mg plus daily oral vortioxetine 10 mg (n = 39), or IV placebo plus daily oral placebo (n = 41). In the placebo lead-in period, patients improved slightly by 0.6 MADRS-6 point; however, at day 1 after randomization, both treatment groups had improved by approximately 3 MADRS-6 points (mean difference = -0.8; P = 0.263), the study thus not meeting its primary endpoint. Similar results were seen for other outcomes except a numerically larger improvement in anxiety symptoms with vortioxetine vs placebo. Pharmacokinetic data confirmed that IV vortioxetine facilitated reaching steady-state plasma concentration within 24 h. IV plus oral vortioxetine was well tolerated, with low levels of nausea as the most common adverse event.