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.

Pitfalls and challenges associated with phenoconversion in forensic toxcicology.

PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.

Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study.

OBJECTIVE: Paroxetine has been demonstrated to undergo gestation-related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. METHODS: A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20-60 ng/ml. KEY FINDINGS: A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultrarapid (UM) phenotype subjects possessed trough levels below 20 ng/ml (73-76%) compared to extensive metabolisers (EM) (51-53%). CONCLUSIONS: For all phenotypes studied, there was a requirement for daily doses in excess of the standard 20 mg dose throughout gestation. For EM, a dose of 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3 is suggested to be optimal. For poor metabolisers (PM), a 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3 is suggested to be optimal. For UM, a 40 mg daily dose throughout gestation is suggested to be optimal.

Psychopharmacology and ethnicity: A comparative study on Senegalese and Italian men.

Objectives: Ethnicity represents a crucial factor in influencing response to psychotropic drugs. Some data indicate that functional polymorphisms of two candidate genes of the serotonin (5-HT) transporter (SERT) may affect the response to selective 5-HT reuptake inhibitors (SSRIs). The present study aimed to compare the platelet SERT, through the specific [3H]paroxetine ([3H]Par) binding, and plasma oxytocin (OT) levels in 20 Senegalese and in 20 Italian men.Methods: No subjects had family or personal history of any major psychiatric disorder, or had ever regularly taken psychotropic drugs, or were suffering from any physical illness.Results: Senegalese men showed statistically significant higher density (Bmax, fmol/mg protein, mean ± SD) of [3H]Par binding sites (2105.00 ± 473.15 vs 1139.85 ± 213.58, P < 0.001), as well as more elevated plasma OT levels (pg/ml, mean ± SD) (OT: 18.08 ± 4.46 vs 6.62 ± 2.91) than Italian men.Conclusions: These differences, possibly due to genetic or dietary reasons, or even to gender, might affect the response to psychopharmacological compounds. Our findings would suggest specific caution when administering psychotropic compounds to non-European individuals, and the need of further studies in this emerging field of neuropsychopharmacology.

Physiologically-Based Pharmacokinetic Modeling for the Prediction of CYP2D6-Mediated Gene-Drug-Drug Interactions.

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interactions (DDIs) in different CYP2D6 genotypes using physiologically-based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6-mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan-duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio (Rpred/obs ) 1.38-1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan-paroxetine interaction, an Rpred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene-drug-drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.

Impact of Lipid Partitioning on the Design, Analysis, and Interpretation of Microsomal Time-Dependent Inactivation.

Nonspecific drug partitioning into microsomal membranes must be considered for in vitro-in vivo correlations. This work evaluated the effect of including lipid partitioning in the analysis of complex TDI kinetics with numerical methods. The covariance between lipid partitioning and multiple inhibitor binding was evaluated. Simulations were performed to test the impact of lipid partitioning on the interpretation of TDI kinetics, and experimental TDI datasets for paroxetine (PAR) and itraconazole (ITZ) were modeled. For most kinetic schemes, modeling lipid partitioning results in statistically better fits. For MM-IL simulations (KI,u = 0.1 µM, kinact = 0.1 minute-1), concurrent modeling of lipid partitioning for an fumic range (0.01, 0.1, and 0.5) resulted in better fits compared with post hoc correction (AICc: -526 vs. -496, -579 vs. -499, and -636 vs. -579, respectively). Similar results were obtained with EII-IL. Lipid partitioning may be misinterpreted as double binding, leading to incorrect parameter estimates. For the MM-IL datasets, when fumic = 0.02, MM-IL, and EII model fits were indistinguishable (δAICc = 3). For less partitioned datasets (fumic = 0.1 or 0.5), the inclusion of partitioning resulted in better models. The inclusion of lipid partitioning can lead to markedly different estimates of KI,u and kinact A reasonable alternate experimental design is nondilution TDI assays, with post hoc fumic incorporation. The best fit models for PAR (MIC-M-IL) and ITZ (MIC-EII-M-IL and MIC-EII-M-Seq-IL) were consistent with their reported mechanism and kinetics. Overall, experimental fumic values should be concurrently incorporated into TDI models with complex kinetics, when dilution protocols are used.

Prediction of drug-drug interactions using physiologically-based pharmacokinetic models of CYP450 modulators included in Simcyp software.

In recent years, physiologically based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics. It has been demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software. The aim of this report was to establish confidence in each CYP-specific modulator file so they can be used in the future for the prediction of DDIs involving new victim compounds. Our evaluation of these PBPK models suggested that they can be successfully used to evaluate DDIs in untested scenarios. The only noticeable exception concerned a quinidine inhibitor model that requires further improvement. Additionally, other important aspects such as model validation criteria were discussed.

Polymorphism in CYP2D6 affects the pharmacokinetics and dose escalation of paroxetine controlled-release tablet in healthy Chinese subjects.

PURPOSE: This study evaluated the effects of CYP2D6 polymorphisms on the pharmacokinetics and dose escalation of controlled-release paroxetine over the dose range of 12.5 - 37.5 mg in healthy Chinese subjects. MATERIALS AND METHODS: This was a phase I, open-label, single-dose, three-period crossover study in which 12 healthy subjects received single oral doses of 12.5, 25, and 37.5 mg paroxetine controlled-release tablets with 10-day washout between doses. Serial venous blood samples were collected for 96 hours after study-drug administration and analyzed with LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Pharmacokinetic parameters of paroxetine were calculated using noncompartmental analysis with WinNonlin software. The linearity of paroxetine pharmacokinetics was assessed using a linear mixed-effect model. RESULTS: The exposure for paroxetine with regard to mean AUC0-inf in the extensive metabolizer (EM) group was 10.3-, 3.6-, and 3.2-fold lower at the doses of 12.5, 25, and 37.5 mg paroxetine, respectively, than that in the intermediate metabolizer (IM) group. There was no apparent dose proportionality over the range of 12.5 - 37.5 mg in either the EM or IM groups. From 12.5 to 25 mg paroxetine, the mean ratios of Cmax/dose and AUC0-inf/dose were 2.04 and 2.40 in the EM group and 0.93 and 1.00 in the IM group, respectively. From 12.5 to 37.5 mg paroxetine, the mean ratios of Cmax/dose and AUC0-inf/dose were 4.04 and 4.08 in the EM group and 1.60 and 1.82 in the IM group, respectively. CONCLUSION: The pharmacokinetics and dose escalation of controlled-release paroxetine after a single administration over the dose range of 12.5 - 37.5 mg were affected by CYP2D6 polymorphisms. The increase of drug exposure associated with an increase in the paroxetine dose was more pronounced in the CYP2D6 EMs than in the IMs.
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The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.

PURPOSE: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. METHOD: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. RESULTS: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. CONCLUSION: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation. Copyright © 2017 John Wiley & Sons, Ltd.

Single- and multiple-dose pharmacokinetics and tolerability of a paroxetine controlled-release tablet in healthy Chinese subjects
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OBJECTIVES: To evaluate the pharmacokinetics of paroxetine controlled-release (CR) tablets after single and multiple oral administrations and to evaluate its safety profile in healthy Chinese subjects. METHODS: This was a phase 1, open-label, single- and multiple-dose combined study. All 12 healthy subjects received a single oral dose of 25-mg paroxetine CR, followed by a washout period of 5 days. Then, the subjects received multiple oral doses of 25-mg paroxetine CR for 14 consecutive days. Serial venous blood samples were collected 96 hours after single dosing and 24 hours after the last dose in multiple-dosing. Blood samples were analyzed using LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated via noncompartmental analysis using the WinNonlin software (Pharsight Corp., Mountain View, CA, USA). RESULTS: For both single- and multiple-dose regimens, a lag time of ~ 4 hours was observed before the absorption of paroxetine CR tablet with a tmax of ~ 7 - 9 hours. From single- to multiple-dose regimens, the mean Cmax increased from 7.08 to 36.95 ng/mL, the mean AUC0-24h increased from 100.91 to 706.75 h×ng/mL, and the mean t1/2 increased from 12.3 to 83.6 hours (all p < 0.05). The point estimate and 90% confidence intervals of the Ctrough ratio indicated that the concentration of paroxetine reached steady state after 14 days of repeated dosing. The point estimate of the accumulation factor indicated that the extent of drug exposure at steady state was ~ 9 times that of single dosing. All reported adverse events were considered to be mild. CONCLUSIONS: Paroxetine CR tablet is absorbed with a delay of ~ 4 hours after oral administration, and the accumulation factor is ~ 9 at steady state. Paroxetine CR tablet is well tolerated by healthy Chinese subjects.
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Influence of the selective antagonist of the NR2B subunit of the NMDA receptor, traxoprodil, on the antidepressant-like activity of desipramine, paroxetine, milnacipran, and bupropion in mice.

Pre-clinical and clinical studies indicated that a blockade of the NMDA receptor complex creates new opportunities for the treatment of affective disorders, including depression. The aim of the present study was to assess the influence of traxoprodil (10 mg/kg) on the activity of desipramine (10 mg/kg), paroxetine (0.5 mg/kg), milnacipran (1.25 mg/kg), and bupropion (10 mg/kg), each at sub-therapeutic doses. Moreover, brain levels of traxoprodil and tested agents were determined using HPLC. The obtained results were used to ascertain the nature of occurring interaction between traxoprodil and studied antidepressants. The experiment was carried out on naïve adult male Albino Swiss mice. Traxoprodil and other tested drugs were administered intraperitoneally. The influence of traxoprodil on the activity of selected antidepressants was evaluated in forced swim test (FST). Locomotor activity was estimated to exclude false positive/negative data. To assess the influence of traxoprodil on the concentration of used antidepressants, their levels were determined in murine brains using HPLC. Results indicated that traxoprodil potentiated activity of all antidepressants examined in FST and the observed effects were not due to the increase in locomotor activity. Only in the case of co-administration of traxoprodil and bupropion, increased bupropion concentrations in brain tissue were observed. All tested agents increased the traxoprodil levels in the brain. Administration of a sub-active dose of traxoprodil with antidepressants from different chemical groups, which act via enhancing monoaminergic transduction, caused the antidepressant-like effect in FST in mice. The interactions of traxoprodil with desipramine, paroxetine, milnacipran, and bupropion occur, at least partially, in the pharmacokinetic phase.

Short-Term Safety of Paroxetine and Sertraline in Breastfed Infants: A Retrospective Cohort Study from a University Hospital.

OBJECTIVE: Primary pharmacological agents for depression and anxiety disorders are antidepressants, especially selective serotonine reuptake inhibitors. The aim of this study was to examine the features and prevalence of adverse effects of paroxetine and sertraline in breastfed infants. METHODS: The study had a retrospective cohort design. Five-year clinical data of 72 patients were included in the study. Psychiatric diagnoses were ascertained by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. RESULTS: The prevalence rate of adverse events in the infants was 12.5%. Insomnia (88.9%), restlessness (55.6%), and constant crying (22.2%) were the most frequent adverse events. A switch between paroxetine and sertraline performed in five patients, who reported an adverse event in their breastfed infants, resulted in cessation of the adverse events. CONCLUSION: The results suggest that the prevalence rate of adverse events in the infants exposed to sertraline or paroxetine is relatively low and mostly mild.

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine.

Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder: a population pharmacokinetic analysis.

OBJECTIVE: Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach. METHODS: This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine. CYP2D6*1, *2, *5, *10, and *41 polymorphisms were observed. A total of 306 steady-state concentrations for paroxetine were collected from the patients. A nonlinear mixed-effects model identified the apparent Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of paroxetine; the covariates included CYP2D6 genotypes, patient age, body weight, sex, and daily paroxetine dose. RESULTS: The allele frequencies of CYP2D6*1, *2, *5, *10, and *41 were 39.4, 14.5, 4.5, 41.1, and 0.6%, respectively. There was no poor metabolizer who had two nonfunctional CYP2D6*5 alleles. A one-compartment model showed that the apparent Km value was decreased by 20.6% in patients with the CYP2D6*10/*10 genotype in comparison with the other CYP2D6 genotypes. Female sex also influenced the apparent Km values. No PK parameters were affected by the presence of one CYP2D6*5 allele. CONCLUSION: Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.

Pharmacokinetics and safety of paroxetine controlled-release tablet in healthy Chinese subjects: a single-dose three-period crossover study.

OBJECTIVES: To evaluate the pharmacokinetics of paroxetine controlledrelease tablets after single oral administrations and its safety profile in healthy Chinese subjects. METHODS: This was a phase I, openlabel, single-dose, three-period crossover study in which 12 healthy subjects received single oral doses of 12.5, 25, 37.5 mg paroxetine controlled-release tablets with 10-day washout between doses. Serial venous blood samples were collected for 96 hours after study drug administration and analyzed with LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated using non-compartmental analysis with Win-Nonlin software. RESULTS: The absorption of controlled-release paroxetine was delayed with a median tmax of 8 - 10 hours and the mean t1/2 was 12 - 14 hours across all doses. Over the dose range of 12.5 - 37.5 mg, the mean Cmax increased from 2.62 to 15.13 ng/mL and AUC0-∞ increased from 63.56 to 404.91 h×ng/mL. The 90% CI for the ratio of dose-normalized mean values of Cmax and AUC were not contained within the criteria limits, indicating a greater than doseproportional increase. All reported adverse events were considered to be mild. CONCLUSIONS: Plasma exposure of controlled-release paroxetine increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. Paroxetine controlled-release tablet was well tolerated in healthy Chinese subjects.

Deuterated Drugs.

Many drugs are carbon-based, and carbon-hydrogen bonding is particularly relevant for understanding important properties of drug molecules. Deuteration refers to the selective replacement of protium hydrogen isotope atoms in small-molecule drugs with deuterium hydrogen isotope atoms. Deuteration of a drug is most likely to affect pharmacokinetic properties, such as metabolism, rather than its pharmacodynamic effects. For this reason, the metabolism of certain drugs may be favorably influenced when deuterium is substituted for protium, resulting in improved safety, tolerability, or efficacy. Examples of deuterated drugs that have been evaluated in clinical studies include paroxetine, tetrabenazine, and dextromethorphan.

Exposure-outcome analysis in depressed patients treated with paroxetine using population pharmacokinetics.

PURPOSE: This study investigated population pharmacokinetics of paroxetine, and then performed an integrated analysis of exposure and clinical outcome using population pharmacokinetic parameter estimates in depressed patients treated with paroxetine. PATIENTS AND METHODS: A total of 271 therapeutic drug monitoring (TDM) data were retrospectively collected from 127 psychiatric outpatients. A population nonlinear mixed-effects modeling approach was used to describe serum concentrations of paroxetine. For 83 patients with major depressive disorder, the treatment response rate and the incidence of adverse drug reaction (ADR) were characterized by logistic regression using daily dose or area under the concentration-time curve (AUC) estimated from the final model as a potential exposure predictor. RESULTS: One compartment model was developed. The apparent clearance of paroxetine was affected by age as well as daily dose administered at steady-state. Overall treatment response rate was 72%, and the incidence of ADR was 30%. The logistic regression showed that exposure predictors were not associated with treatment response or ADR in the range of dose commonly used in routine practice. However, the incidence of ADR increased with the increase of daily dose or AUC for the patients with multiple concentrations. CONCLUSION: In depressed patients treated with paroxetine, TDM may be of limited value for individualization of treatment.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men.

We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40 mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects.All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.

Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems.

PURPOSE: This study evaluated the effects of cytochrome P450 (CYP) 2D6 polymorphisms on the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects and used paroxetine as a tool drug to compare the performance of traditional phenotype and activity score systems. METHODS: Pharmacokinetic data were evaluated in 24 subjects who received a single oral dose of 25 mg controlled-release paroxetine. Plasma paroxetine concentrations were measured by LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Subjects were classified by two systems of phenotype prediction. In the traditional phenotype system, subjects were classified as extensive metabolizers or intermediate metabolizers; in the activity score system, subjects were divided into four activity groups. Analysis of variance testing was applied to estimate the effects of CYP2D6 polymorphisms on the pharmacokinetics of paroxetine. RESULTS: With the traditional phenotype system, significant differences were observed in the following pharmacokinetic parameters of paroxetine: t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F (all P < 0.05). The AUC or exposure of paroxetine was about 3.5-fold higher in the intermediate metabolizer group than in the extensive metabolizer group. With the activity score system, significant differences were observed in the t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F among the four different activity score groups (all P < 0.05). We found that the AUC of paroxetine decreased by around one half as the activity score increased by 0.5. CONCLUSION: The pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.