Plasma Concentrations Of Paroxetine Research Articles

Effects of personality on the association between paroxetine plasma concentration and response.

BackgroundWe studied the differences between groups that were divided according to personality characteristics with respect to the relationship between drug concentration and symptom improvement.MethodsA total of 120 patients with major depressive disorder were treated with paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery–Åsberg Depression Rating Scale (MADRS) was used to evaluate the patients. Patients’ paroxetine plasma concentrations at week 6 were measured. Their personalities were evaluated by the Temperament and Character Inventory (TCI) at the first visit. We divided the patients into two groups according to the median of each TCI dimension. We compared the responder rate between “high” and “low” groups in each TCI dimension and analyzed Pearson’s correlation coefficients of paroxetine plasma concentration and MADRS-improvement rate.ResultsA total of 62 patients completed the TCI. Low-novelty-seeking, high-harm-avoidance, low-reward-dependence, and low-self-directedness groups exhibited significant negative correlations between paroxetine plasma concentration and MADRS improvement. Among the groups with combined personality traits, the high-harm-avoidance and low-self-directedness groups showed a markedly significant negative correlation.ConclusionPatients with depression exhibiting specific personality traits, especially those with high harm-avoidance and low self-directedness scores, exhibited a significant negative association between paroxetine plasma concentration and MADRS-improvement rate. Therefore, a lower dose might be suitable for patients with specific personality traits.

Therapeutic reference range for plasma concentrations of paroxetine in patients with major depressive disorders.

We investigated the relationship between plasma concentrations of paroxetine and the therapeutic effect of the drug, and we evaluated the therapeutic reference range for plasma concentration of paroxetine in patients with major depressive disorders (MDD). In this study, 120 patients with MDD were treated with 10-40 mg/d of paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate the patients at 0, 1, 2, 4, and 6 weeks. At the 6-week treatment time point, the patients were divided into 7 groups according to their paroxetine plasma concentrations in increments of 20 ng/mL. We used an analysis of variance and a χ test to define the therapeutic reference range for plasma paroxetine concentrations. We used 50% as the cutoff values for the percentage of MADRS improvement to determine the responder rates, and we defined remitters as patients with MADRS scores <10 at the 6-week treatment time point. We analyzed the responder and remitter rates of the patients according to their plasma paroxetine concentrations: 20 ng/mL, 40 ng/mL, and 60 ng/mL using the χ test. According to the results of the χ test in the responder rates, the 20-60 ng/mL plasma paroxetine group showed the highest effect size. The results of this study suggested that a range of 20-60 ng/mL is the therapeutic reference range for concentrations of paroxetine in plasma in patients with MDD.

The influence of 5-HTTLPR genotype on the association between the plasma concentration and therapeutic effect of paroxetine in patients with major depressive disorder.

IntroductionThe efficacy of treatment with selective serotonin reuptake inhibitors in patients with major depressive disorder (MDD) can differ depending on the patient's serotonin transporter-linked polymorphic region (5-HTTLPR) genotype, and the effects of varying plasma concentrations of drugs can also vary. We investigated the association between the paroxetine plasma concentration and clinical response in patients with different 5-HTTLPR genotypes.MethodsFifty-one patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate patients at 0, 1, 2, 4, and 6 weeks. The patients' paroxetine plasma concentrations at week 6 were measured using high-performance liquid chromatography. Additionally, their 5-HTTLPR polymorphisms (alleles S and L) were analyzed using a polymerase chain reaction with specific primers. We divided the participants into two groups based on their L haplotype: the SS group and the SL and LL group. We performed single and multiple regression analyses to investigate the associations between MADRS improvement and paroxetine plasma concentrations or other covariates for each group.ResultsThere were no significant differences between the two groups with regard to demographic or clinical data. In the SS group, the paroxetine plasma concentration was significantly negatively correlated with improvement in MADRS at week 6. In the SL and LL group, the paroxetine plasma concentration was significantly positively correlated with improvement in MADRS at week 6 according to the results of the single regression analysis; however, it was not significantly correlated with improvement in MADRS at week 6 according to the results of the multiple regression analysis.ConclusionAmong patients with MDD who do not respond to paroxetine, a lower plasma concentration or a lower oral dose of paroxetine might be more effective in those with the SS genotype, and a higher plasma concentration might be more effective in those with the SL or LL genotype.

Comparison of lithium, aripiprazole and olanzapine as augmentation to paroxetine for inpatients with major depressive disorder.

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatments for major depressive disorders (MDD). It has been reported, however, that 30-40% of patients with MDD who received SSRIs failed to respond to treatment. Use of lithium (Li) to augment SSRIs seems to be the most common strategy in such cases. It was recently demonstrated that atypical antipsychotics are effective augmentation agents in MDD. Here, we present a randomized controlled study that compared augmentation with Li, olanzapine (OLA) or aripiprazole (ARI) in paroxetine-refractory patients with MDD. Participants were 30 patients who met Diagnostic and Statistical Manual of Mental Disorders IV criteria for MDD and refractory to paroxetine treatment. Treatment with Li, OLA or ARI was added to paroxetine in a randomized protocol for 4 weeks. We defined the patients whose scores on the Hamilton Rating Scale for Depression decreased 50% or more as responders. Two patients dropped out because of adverse effects. Response rates to Li, OLA or ARI augmentation were 4/10 (40%), 3/10 (30%) and 4/10 (40%), respectively. In addition, Li, OLA and ARI did not influence plasma paroxetine concentrations. We concluded that OLA or ARI could be used as alternatives to Li as options for patients who do not respond to paroxetine treatment.

P.1.g.074 Plasma concentrations of paroxetine among treatment responder inpatients at week one and before discharge

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with cognitive impairment and major neuropathologic hallmark of amyloid-beta (Aβ) peptides. Risperidone, an atypical antipsychotic, can improve concentration and cognitive deficit in schizophrenia patients. In this study, behavior tests including Morris Water Maze test, Step-through passive avoidance test, Open Field test, Step-Down test, Hole-Board test and Novel object recognition test were preformed to examine the effect of Risperidone on Aβ1-42-induced cognitive dysfunction in both long-term and short-term memory. Furthermore, ELISA assay was conducted to measure the levels of Aβ1-42, BACE1 and p-Tau in the hippocampus and cortex. Moreover, primary cortical neuron was cultured in vitro, and the cell viability, mitochondrial membrane potential, and the level of p-Akt, GSK3β and Caspase-3 protein were measured. For behavior tests, the results showed that Risperidone significantly reversed the Aβ1-42-induced dysfunction in learning, memory, locomotor activity and exploratory behavior. As detected by ELISA assay, risperidone decreased the levels of Aβ1-42, BACE1 and p-Tau in the hippocampus and cortex of AD model mice. Biochemical assay showed that Risperidone reversed the Aβ1-42-induced decrease of cell viability and mitochondrial membrane potential in cultured cortical neurons. The expression of p-Akt was increased, whereas the expression of GSK3β and Caspase-3 were decreased. These results suggested that Risperidone may be used as a promising candidate for AD treatment, for its effects of inhibiting Aβ generation and improving cognitive impairment in mice.

Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing

Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9±2.6 h) and a low bioavailability (31±15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first-pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders.

Randomized Open-Label Drug-Drug Interaction Trial of Dextromethorphan/Quinidine and Paroxetine in Healthy Volunteers

The novel combination of dextromethorphan (DM) and quinidine (Q) [DMQ] has been extensively studied in well controlled clinical trials as treatment for pseudobulbar affect (PBA), and is the first US Food and Drug Administration (FDA)-approved treatment for this indication. The approved dosage of DMQ is DM 20 mg and Q 10 mg twice daily. DM is metabolized via cytochrome P450 2D6 (CYP2D6); Q is a CYP2D6 inhibitor used to increase DM plasma concentrations. Paroxetine is both a substrate and inhibitor of CYP2D6. This trial evaluated the effect of DMQ at a dose of DM 30 mg and Q 30 mg twice daily on the steady-state pharmacokinetics of paroxetine 20 mg daily and the effects of paroxetine on the steady-state pharmacokinetics of DMQ in healthy volunteers. This was an open-label, randomized, parallel-group, 20-day trial. Drug plasma concentrations were analysed following monotherapy and concomitant (DMQ + paroxetine) therapy. Participants were 27 healthy adults who were randomized in a 1 : 1 fashion to one of two groups. Group 1 received paroxetine 20 mg once daily for 12 days to attain steady state, at which point DMQ 30 mg/30 mg twice daily was added for 8 days. Group 2 received DMQ 30 mg/30 mg twice daily for 8 days to attain steady state, at which point paroxetine 20 mg once daily was added for 12 days. The primary endpoints were the 90% confidence intervals (CIs) for the ratio of the area under the plasma concentration-time curve (AUC) during concomitant therapy versus monotherapy. Safety and tolerability measures including adverse events (AEs) were also assessed. The 90% CIs of the AUCs were outside of the predefined range [0.80, 1.25] for all analytes, indicating a drug-drug interaction. In group 1 (n = 14), addition of DMQ to paroxetine resulted in a 30% increase in mean plasma exposure of paroxetine (AUC up to 24 hours). In group 2 (n = 13), addition of paroxetine to DMQ resulted in increases in mean plasma exposure (AUC up to 12 hours) of 50% for DM and 40% for Q, and a decrease of 12.3% for dextrorphan, the metabolite of DM. The incidence of AEs was higher with paroxetine monotherapy and combination therapy, compared with DMQ given alone (30.8% with DMQ alone vs 83.3% following addition of paroxetine, and 78.6% with paroxetine alone vs 64.3% following addition of DMQ). Three subjects discontinued due to AEs, and no serious AEs were reported. The addition of DMQ 30 mg/30 mg twice daily to paroxetine increased steady-state paroxetine plasma concentrations and addition of paroxetine to DMQ 30 mg/30 mg twice daily increased steady-state plasma concentrations of DM and Q, indicating a potential interaction. Thus, patients should be monitored for AEs and dosage adjustment considered when combining these two agents.

日本人健康成人男性におけるMSG203錠およびパキシル&lt;sup&gt;&amp;reg;&lt;/sup&gt;錠（パロキセチン塩酸塩水和物）の単回経口投与後の生物学的同等性の検討 ―CYP2D6 Genotypeによる詳細比較―

MSG203 was developed by Meiji Seika Pharma Co., Ltd. as a generic drug of paroxetine hydrochloride hydrate (Paxil® Tablets). Paroxetine is mainly metabolized by CYP2D6.Therefore, in addition to the evaluation of bioequivalence between MSG203 and Paxil®, the effects of CYP2D6 polymorphism on the pharmacokinetic (PK) parameters of plasma paroxetine were also investigated.Ninety-six Japanese healthy subjects aged 20-35 years participated in the study. The study was performed in 3 different groups: MSG5 group compared 2 tablets of MSG203 5 mg versus 1 tablet of Paxil® 10 mg; MSG10 group compared 1 tablet of MSG203 10 mg versus 1 tablet of Paxil® 10 mg; and MSG20 group compared 1 tablet of MSG203 20 mg versus 1 tablet of Paxil® 20 mg. Bioequivalence between MSG203 and Paxil® was confirmed in all three groups. The safety profiles of both drugs were also similar. The PK parameters after a single oral dose of MSG203 20 mg in subjects with different CYP2D6 phenotypes were as follows. Mean Cmax (ng/mL) of paroxetine was 0.78 in ultra-rapid metabolizers (UM; n=1), 5.82 in extensive metabolizers (EM; n=24), and, 18.60 in intermediate metabolizers (IM; n=4). Mean AUC t (ng•h/mL) was 7.93 in UM, 88.52 in EM, and 495.61 in IM. Similar PK profiles in these phenotypes were confirmed after a single oral dose of Paxil®.In this study, plasma concentrations of paroxetine were very low because of the high clearance profile in UM subjects. Generally, inadequate treatment would occur in patients with the UM phenotype of CYPs. However, information on the PK profiles in different CYP phenotypes is insufficient. Evaluation of the PK profiles of drugs in different CYP phenotypes provides valuable information for clinical use of drugs that are metabolized by polymorphic enzymes.

Inverse correlation between clinical response to paroxetine and plasma drug concentration in patients with major depressive disorders

There are few data concerning a clear relationship between the clinical effect of paroxetine and plasma drug concentrations, although therapeutic ranges have been established for some tricyclic antidepressants. In this study, 120 patients with major depressive disorders were treated with 10-40 mg/day of paroxetine for 6 weeks, and a total of 89 patients completed the protocol. A clinical evaluation using the Montgomery-Asberg Depression Rating Scale (MADRS) was performed at 0, 1, 2, 4 and 6 weeks. Significant correlations were found between the plasma concentrations of paroxetine and the percentage improvement in the total MADRS scores (r = -0.282, p < 0.01) and the final MADRS scores at 6 weeks (r = 0.268, p < 0.05). The conventional receiver-operating-characteristic curve showed the fraction of true positive results and false negative results for various cut-off levels of paroxetine concentration for response and remission. The thresholds for both response and remission that gave the maximal sensitivity and specificity for paroxetine concentrations were 64.2 ng/ml. These results suggest that plasma paroxetine concentrations are negatively associated with improvement and that response occurs at the upper threshold of 64.2 ng/ml of paroxetine. These findings should be replicated with a larger patient sample.

Determinants of pharmacodynamic trajectory of the therapeutic response to paroxetine in Japanese patients with panic disorder

The objective of this study was to evaluate genetic and pharmacokinetic factors to establish the pharmacotherapeutic effect of paroxetine (PAX) in patients with panic disorder (PD). Subjects were 65 drug-naïve patients who fulfilled the DSM-IV-TR criteria for PD diagnosis. All subjects were administered PAX (10mg/day) for 4weeks, and PD severity was assessed using the Panic and Agoraphobia Scale (PAS) at baseline and at 2 and 4weeks after initiation of treatment. Plasma PAX concentration was determined by high-performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants and the -1019C/G promoter polymorphism of the serotonin 1A receptor (5-HT(1A)) gene were determined by PCR analysis. Multiple regression analysis revealed that the plasma concentrations of PAX, 5-HTTLPR genotype, and -1019C/G 5-HT(1A) gene polymorphism were significant factors affecting clinical response to PAX (reduction ratio of PAS score) at 2weeks after the initiation of pharmacotherapy. The -1019C/G 5-HT(1A) gene promoter polymorphism, PAS score at baseline, and adverse effects were found to be the significant factors affecting clinical response to PAX at 4weeks after initiation of pharmacotherapy. The present study revealed that plasma concentration of PAX, 5-HTTLPR genotype, -1019C/G 5-HT(1A) genotype, PAS score at baseline, and adverse effects may influence the therapeutic response to PAX in patients with PD.

Association between plasma paroxetine concentration and changes in plasma brain‐derived neurotrophic factor levels in patients with major depressive disorder

Recent studies have implicated brain‐derived neurotrophic factor (BDNF) in the pathophysiology of depression and in the activities of antidepressant drugs. Serum BDNF levels are lower in depressed patients and increase in response to antidepressant medications; however, no studies have examined the association between plasma concentrations of antidepressant drugs and plasma BDNF levels. We assessed plasma BDNF levels and paroxetine concentrations in 45 patients with major depression who were being treated with paroxetine. Plasma samples were collected between 10:00 h and 12:00 h at baseline and after 1, 2 and 6 weeks of treatment. The BDNF level and paroxetine concentration of each sample were measured via enzyme immunoassay and high‐performance liquid chromatography, respectively. Plasma BDNF levels increased after 2 and 6 weeks of paroxetine treatment. Plasma BDNF levels were significantly lower in men than in women. Changes in plasma BDNF level were correlated with plasma drug concentration after 2 (r = 0.309, p < 0.05) and 6 weeks (r = 0.329, p < 0.05) but not correlated with plasma drug concentration after 1 week (r = 0.284, ns). Multiple regression analysis confirmed that this change was only significantly correlated with plasma paroxetine concentration after 2 (standardised beta = 0.343, p < 0.05) and 6 weeks (standardised beta = 0.375, p < 0.05). These results suggest that paroxetine treatment increases plasma BDNF levels and that plasma paroxetine levels play an important role in changes in plasma BDNF levels.

No difference in adherence to paroxetine between depressed patients with early remission and those with late remission based on monitoring of plasma paroxetine concentrations

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat both anxiety disorders and depressive disorders. However, nonadherence to SSRIs is a major issue in recurrence. In the present study, we investigated paroxetine adherence in depressed patients by monitoring the plasma paroxetine concentrations between patients with rapid and those with a late response to paroxetine treatment. Twenty inpatients in our university hospital, who met the DSM-IV-TR diagnosis of major depressive disorder in a single episode, were enrolled in the study. Twelve patients (M/F: 7/13, age: 37.4 +/- 10.4 years) were treated with paroxetine (40 mg/day), and all achieved remission (HAMD < or = 7) within at least 12 weeks. We divided the patients into two groups, an early-remission group (HAMD < or = 7 within 4 weeks) and a late-remission group (HAMD < or = 7 within 8-12 weeks). Their dosages of paroxetine were constant because of no emerging adverse effects. Blood samples were obtained on the day the subjects were discharged (B) and 12 weeks after discharge. The paroxetine concentrations in the early-remission group were significantly decreased 12 weeks after discharge, and no difference was found between the early- and late-remission groups. These results suggest that adherence to paroxetine was independent of the duration of the depressive state suffered by the patients. Clinicians always take their cautions for the adherence to paroxetine regardless of the clinical time courses the patients recovering from their depressive symptoms.

Effect of Cytochrome P450 2D6 Genotype on Maternal Paroxetine Plasma Concentrations during Pregnancy

Increasing numbers of women in childbearing years are treated with antidepressants. Concerns regarding fetal exposure to medication has led to large studies on drug effects on birth outcome and on the risk of congenital anomalies. The risk of adverse effects due to paroxetine use during pregnancy has been associated with the extent of exposure. Nevertheless, few studies have covered dosing aspects in order to minimize fetal antidepressant exposure while limiting the risk of treatment failure. Essential pharmacokinetic data in pregnancy are lacking, even regarding paroxetine, one of the most commonly used antidepressants. We examined the changes of maternal paroxetine concentrations during pregnancy in relation to cytochrome P450 (CYP) 2D6 genotype. An observational cohort study was conducted in 74 pregnant women aged from 25 to 45 years treated with paroxetine during pregnancy. Blood samples and information on dosing, weight, smoking and mood were provided at 16-20, 27-31 and 36-40 weeks of pregnancy. Samples were analysed for paroxetine plasma concentrations and CYP2D6 genotype. Women who were genotyped as extensive metabolizers (EMs) or ultra-rapid metabolizers (UMs) for CYP2D6 (EM n = 43; UM n = 1) showed steadily decreasing plasma paroxetine concentrations during the course of pregnancy, with a decrease of 0.3 microg/L (95% CI -0.58, -0.07) for each week of pregnancy. In contrast, plasma paroxetine concentrations of intermediate metabolizers (IMs [n = 25]) and poor metabolizers (PMs [n = 5]) increased during pregnancy, resulting in an increase of 0.82 microg/L (95% CI 0.42, 1.22) for each week of pregnancy. Weight gain, maternal age or smoking did not influence plasma drug concentrations. Decreasing plasma concentrations in EMs are in accordance with induced CYP2D6 activity during pregnancy. Accumulation of paroxetine in women with impaired CYP2D6 metabolism may be explained by competition with an endogenous substrate. In EMs/UMs the depressive symptoms increased significantly during the course of pregnancy, while in the IM/PM group these did not change. Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient's CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy [trialregister.nl Identifier ISRCTN25383361].

Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder

The objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD). Plasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS). Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R(2) = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 - 1.2 x [plasma concentration of PAX (ng/ml)] - 33.0 x (L/S = 1, S/S = 0) - 21.8 x (with comorbid physical illness = 1, without comorbid physical illness = 0). The high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.

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Concentrações plasmáticas de paroxetina em pacientes adultos e idosos com depressão

INTRODUÇÃO: O efeito do envelhecimento nas concentrações plasmáticas em estado de equilíbrio da paroxetina foi investigado em 136 pacientes com depressão, tratados com doses variando entre 10 e 120 mg/dia de paroxetina. MÉTODOS: Os pacientes foram separados em três grupos: com idade até 64 anos (idade média ± desvio padrão: 41,7±12,6 anos; n = 44), entre 65 e 79 anos (72,8±4,7 anos; n = 64), e com mais de 80 anos (82,8±3,3 anos; n = 28). As doses de paroxetina foram normalizadas para 20 mg/dia. Amostras de sangue foram coletadas em condições de estado de equilíbrio. Os níveis plasmáticos de paroxetina foram medidos por cromatografia gasosa - espectrometria de massa. As funções hepática e renal foram medidas por testes laboratoriais clínicos estandardizados. RESULTADOS: Uma grande variabilidade interindividual dos níveis plasmáticos de paroxetina (37 vezes) foi medida para uma mesma dose. A média dos níveis plasmáticos de paroxetina corrigida para uma dose diária de 20 mg foi 87% maior no grupo com mais de 80 anos (56,4±64,1 ng/mL; p &lt; 0,05) e 57% maior no grupo com idades entre 65 e 79 anos (46,7±33,4 ng/mL; p &lt; 0,001) quando comparada com a média dos pacientes com menos de 64 anos (29,9±11,9 ng/mL). A idade foi correlacionada significativamente com os níveis plasmáticos de paroxetina (r = 0,21, p &lt; 0,05) CONCLUSÃO: A redução de doses da paroxetina em pacientes idosos parece justificada.

High Plasma Concentrations of Paroxetine Impede Clinical Response in Patients With Panic Disorder

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.

Effect of Itraconazole on Pharmacokinetics of Paroxetine: The Role of Gut Transporters

A recent in vitro study has shown that paroxetine is a substrate of P-glycoprotein. However, there was no in vivo information indicating the involvement of P-glycoprotein on the pharmacokinetics of paroxetine. The aim of this study was to examine the effects of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics of paroxetine. Two 6 day courses of either 200 mg itraconazole daily or placebo with at least a 4 week washout period were conducted. Thirteen volunteers took a single oral 20 mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 hours after the dosing. Compared with placebo, itraconazole treatment significantly increased the peak plasma concentration (Cmax) of paroxetine by 1.3 fold (6.7 +/- 2.5 versus 9.0 +/- 3.3 ng/mL, P < 0.05) and the area under the plasma concentration-time curve from zero to 48 hours [AUC (0-48)] of paroxetine by 1.5 fold (137 +/- 73 versus 199 +/- 91 ng*h/mL, P < 0.01). Although elimination half-life differed significantly (16.1 +/- 3.4 versus 18.8 +/- 5.9 hours, P < 0.05), the alteration was small (1.1 fold). The present study demonstrated that the bioavailability of paroxetine was increased by itraconazole, suggesting a possible involvement of P-glycoprotein in the pharmacokinetics of paroxetine.

Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects

Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine. Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing. Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (C(max)) of paroxetine, by 1.9-fold (6.4 +/- 2.4 versus 12.1 +/- 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0-48)] of paroxetine by 2.5-fold (127 +/- 67 vs 318 +/- 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 +/- 2.4 vs 22.7 +/- 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than C(max )or AUC. The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.

Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study

To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT. (123)I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc. Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. (123)I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E (max) model. Mean SERTocc values were 66.4 +/- 9.5% in midbrain, 63.0 +/- 9.6% in thalamus, and 61.3 +/- 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 +/- 0.15; thalamus = 0.85 +/- 0.13; striatum = 0.70 +/- 0.07) and healthy volunteers (midbrain = 1.19 +/- 0.22; thalamus = 0.96 +/- 0.14; striatum = 0.67 +/- 0.15). The E (max) model returned a SERTocc(max) = 70.5% and a Cp(50) = 2.7 ng/ml. Using (123)I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E (max) model is suitable for the study of paroxetine Cp relationship to (123)I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic-pharmacodynamic relationships in drug development.