Optimizing the individual dosing of paroxetine in major depressive disorder with therapeutic drug monitoring.

INTRODUCTION: Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory. AIMS: This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing. METHODS: Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n = 38), medium-concentration (MC, n = 27), and high-concentration (HC, n = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range. RESULTS: The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations. CONCLUSION: Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients.

Development, optimization and ex-vivo evaluation of a transdermal formulation containing trazodone.

Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.

Developing a machine learning model for predicting venlafaxine active moiety concentration: a retrospective study using real-world evidence.

BACKGROUND: Venlafaxine is frequently prescribed for patients with depression. To control the concentration of venlafaxine within the therapeutic window for the best treatment effect, a model to predict venlafaxine concentration is necessary. AIM: Our objective was to develop a prediction model for venlafaxine concentration using real-world evidence based on machine learning and deep learning techniques. METHOD: Patients who underwent venlafaxine treatment between November 2019 and August 2022 were included in the study. Important variables affecting venlafaxine concentration were identified using a combination of univariate analysis, sequential forward selection, and machine learning techniques. Predictive performance of nine machine learning and deep learning algorithms were assessed, and the one with the optimal performance was selected for modeling. The final model was interpreted using SHapley Additive exPlanations. RESULTS: A total of 330 eligible patients were included. Five influential variables that affect venlafaxine concentration were venlafaxine daily dose, sex, age, hyperlipidemia, and adenosine deaminase. The venlafaxine concentration prediction model was developed using the eXtreme Gradient Boosting algorithm (R2 = 0.65, mean absolute error = 77.92, root mean square error = 93.58). In the testing cohort, the accuracy of the predicted concentration within ± 30% of the actual concentration was 73.49%. In the subgroup analysis, the prediction accuracy was 69.39% within the recommended therapeutic range of venlafaxine concentration within ± 30% of the actual value. CONCLUSION: The XGBoost model for predicting blood concentration of venlafaxine using real-world evidence was developed, guiding the adjustment of regimen in clinical practice.

Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS: This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS: Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS: These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

P-glycoprotein mediates the pharmacokinetic interaction of olanzapine with fluoxetine in rats.

Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) and Mdr1a/b gene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (Cmax, 44.1 ± 5.1 ng/mL in the combination group vs 9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC0-t, 235.8 ± 22.7 h × ng/mL in the combination group vs 47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination group vs 49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased the in vivo exposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cells in vitro as well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A.

Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for Cmax and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC0-∞ , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

BACKGROUND: Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. METHODS: This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. RESULTS: Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). CONCLUSIONS: This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

[Personalized treatment of depression phenotypes: role of trazodone in depression with insomnia]. / Trattamento personalizzato dei fenotipi di depressione: ruolo del trazodone nella depressione con insonnia.

AIM: This paper completes a series of three manuscripts on the clinically relevant evidence of the use of trazodone in major depressive disorder. The first paper provided general clinical guidance on the use of trazodone in major depressive disorder. The second paper evaluated the different clinical scenarios in which trazodone prolonged-release or trazodone Contramid® once-a-day may be more indicated. This third and last paper evaluates the clinically relevant evidence about the use of trazodone in major depressive disorder (MDD) with insomnia. METHODS: Medline and Cochrane Library searches were performed using the keywords 'trazodone' AND 'depression' AND 'insomnia', to identify the most relevant literature on the use of trazodone in patients with MDD and insomnia. European and the United States prescribing information was reviewed as well. More weight was given to the information that was deemed as most relevant for daily clinical practice. RESULTS: Trazodone is an effective medication for patients with MDD and insomnia. DISCUSSION: Trazodone is efficacious for the treatment of a broad array of depressive symptoms and is particularly useful for patients presenting with insomnia as one of the symptoms of depression. CONCLUSIONS: Trazodone improves sleep and depression and is particularly helpful for patients whose symptoms of depression include insomnia.

Influence of Zuojin Pill on the Metabolism of Venlafaxine in Vitro and in Rats and Associated Herb-Drug Interaction.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have a high likelihood of combination usage in patients with depression with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhP450s), especially on CYP2D6, whereas VEN undergoes extensive metabolism by CYP2D6. From this perspective, we investigated the influence of ZJP on the metabolism of VEN in vitro and in rats for the first time. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 µg/ml, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The area under drug concentration-time curve0-24 hour of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2 hours after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated clinical significance needed to be seriously considered. SIGNIFICANCE STATEMENT: Zuojin Pill, a commonly used Chinese herbal medicine, demonstrates significant inhibitory effects on hepatic metabolism and pharmacokinetics of venlafaxine in vitro and in rats mainly through suppression of CYP2D6 activity. The human pharmacokinetic interaction between Zuojin Pill and venlafaxine and its associated clinical significance needs to be seriously considered.

Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults.

The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (Cmax ) and area under the plasma concentration-time curve over 24 hours (AUC0-24 )) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism.

A randomized placebo-controlled trial of bupropion for Cancer-related fatigue: Study design and procedures.

BACKGROUND: Cancer-related fatigue is a significant problem and is associated with poor quality of life. Behavioral interventions include exercise and cognitive-behavioral therapy, which survivors may be unwilling or unable to adopt. Pharmacologic interventions (e.g., selective serotonin reuptake inhibitors) have been disappointing. One potential therapy is the antidepressant bupropion, a norepinephrine-dopamine reuptake inhibitor that targets both inflammation and the hypothalamic-pituitary-adrenal axis. The current study is intended to provide a rigorous test of the efficacy and tolerability of bupropion for cancer-related fatigue. METHODS: A randomized, double-blind, placebo-controlled trial will examine the effects of bupropion on cancer-related fatigue. The trial will be conducted nationwide through the University of Rochester Medical Center (URMC) National Cancer Institute Community Oncology Research Program (NCORP). Disease-free breast cancer survivors (n = 422) who completed chemotherapy and/or radiotherapy 12-60 months previously and report significant fatigue will be randomized 1:1 to receive bupropion (300 mg/day) or placebo. Outcomes will be assessed at baseline and the 12-week follow-up. The primary outcome, fatigue, will be measured with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Secondary outcomes include quality of life, depression, and drug tolerability. Exploratory outcomes include cognition and symptomatology. Potential biological mechanisms and genetic moderators of cancer-related fatigue will also be explored. DISCUSSION: This study is the first placebo-controlled trial to our knowledge to evaluate bupropion for cancer-related fatigue. Positive results could revolutionize the treatment of cancer-related fatigue, as bupropion is safe, inexpensive, widely-available, and may be more tolerable and acceptable for many patients than current, limited treatment options.

Estimation of an Appropriate Dose of Trazodone for Pediatric Insomnia and the Potential for a Trazodone-Atomoxetine Interaction.

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2- to 6-year-old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6- to 12-year-old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12- to 17-year-old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models.

CYP2D1 Gene Knockout Reduces the Metabolism and Efficacy of Venlafaxine in Rats.

Rat CYP2D1 has been considered as an ortholog of human CYP2D6 To assess the role of CYP2D1 in physiologic processes and drug metabolism, a CYP2D1-null rat model was generated with a CRISPR/Cas9 method. Seven base pairs were deleted from exon 4 of CYP2D1 of Sprague-Dawley wild-type (WT) rats. The CYP2D1-null rats were viable and showed no abnormalities in general appearance and behavior. The metabolism of venlafaxine (VLF) was further studied in CYP2D1-null rats. The V max and intrinsic clearance of the liver microsomes in vitro from CYP2D1-null rats were decreased (by ∼46% and ∼57% in males and ∼47% and ∼58% in females, respectively), while the Michaelis constant was increased (by ∼24% in males and ∼25% in females) compared with WT rats. In the pharmacokinetic studies, compared with WT rats, VLF in CYP2D1-null rats had significantly lower apparent total clearance and apparent volume of distribution (decreased by ∼36% and ∼48% in males and ∼23% and ∼25% in females, respectively), significantly increased area under the curve (AUC) from the time of administration to the last time point, AUC from the start of administration to the theoretical extrapolation, and C max (increased by ∼64%, ∼59%, and ∼26% in males and ∼43%, ∼35%, and ∼15% in females, respectively). In addition, O-desmethyl venlafaxine formation was reduced as well in CYP2D1-null rats compared with that in WT rats. Rat depression models were developed with CYP2D1-null and WT rats by feeding them separately and exposing them to chronic mild stimulation. VLF showed better efficacy in the WT depression rats compared with that in the CYP2D1-null rats. In conclusion, a CYP2D1-null rat model was successfully generated, and CYP2D1 was found to play a certain role in the metabolism and efficacy of venlafaxine. SIGNIFICANCE STATEMENT: A novel CYP2D1-null rat model was generated using CRISPR/Cas9 technology, and it was found to be a valuable tool in the study of the in vivo function of human CYP2D6. Moreover, our data suggest that the reduced O-desmethyl venlafaxine formation was associated with a lower VLF efficacy in rats.

Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug-drug interactions and probability of target attainment.

AIMS: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug-drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. METHODS: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)-infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under- or over-exposed, considering established therapeutic targets (15-80 ng/mL). RESULTS: A 1-compartment model with first-order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV-infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton-pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model-based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under-exposed. CONCLUSION: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.

Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects.

Bupropion is an atypical antidepressant of the aminoketone group, structurally related to cathinone, associated with a wide interindividual variability. An extensive pharmacokinetic and pharmacodynamic review of bupropion was performed, also focusing on chemical, pharmacological, toxicological, clinical and forensic aspects of this drug without a limiting period. Bupropion is a chiral, basic, highly lipophilic drug, clinically used as racemate that undergoes extensive stereoselective metabolism. Its major active metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion reach higher plasma concentrations than bupropion. Bupropion exerts its effects mainly by inhibiting dopamine and norepinephrine reuptake and by blocking several nicotinic receptors. Recent reports highlight recreational use of bupropion via intranasal insufflation and intravenous use. Seizures, insomnia, agitation, headache, dry mouth, and nausea are some of the reported adverse effects. Neurologic effects are major signs of intoxication that should be carefully managed. Finally, the characterization of the polymorphic enzymes involved in the metabolism of bupropion is essential to understand factors that may influence the interindividual and intraindividual variability in bupropion metabolite exposure, including the evaluation of potential drug-drug interactions and pharmacogenetic implications.

Choosing among second-generation antidepressant treatments for depressed patients with cardiac diseases.

Objectives: The present paper aimed to assist physicians in the accurate choice among second-generation agents (SGAs) for patients with cardiovascular disease (CVD). Methods: We reviewed the published pharmacokinetic (PK) and pharmacodynamic (PD) clinical data that report potential -or absence of- drug interactions between second-generation agents (SGAs) and CVD drugs most commonly used in cardiology, including antiplatelet drugs and anticoagulants, statins, beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics and the antiarrhythmic drugs amiodarone and digoxin. We also reviewed the cardiovascular safety profile that has been published for each class of SGAs and side effects reported by patients with CVD. Results: Most relevant PK/PD data about SGAs and CVD drugs are based on small studies or detailed case reports. In many cases, the drug interactions are at most assessed in healthy volunteers so that the clinical relevance of findings needs further investigation in patients with CVD. Case reports of serious, sometimes fatal reactions due to concomitant administration of certain drugs require careful consideration. The major cardiac side effects of SGAs include HR increase, postural hypotension and slight prolongation of the intraventricular conduction time and QT interval. On normal dosage of antidepressants, both advanced heart block and ventricular arrhythmias could occur in patients with severe heart disease, together with clinically important loss of myocardial contractile force. Conclusions: Data reported in the present review should help physicians about their decision-making processes that govern SGAs use in CVD patients.

Selective serotonin reuptake inhibitors' passage into human milk of lactating women.

Objective: Selective serotonin reuptake inhibitors are commonly used for the treatment of pregnancy-related and postnatal depression. However, only a few studies have evaluated the passage of these drugs into human milk, often with conflicting results. Here, we sought to evaluate the passage of selective serotonin reuptake inhibitors into human milk in the first days after delivery and their potential association with neonatal outcomes. Study design: The passage of selective serotonin reuptake inhibitors into human milk was expressed both as percentage of milk-to-plasma ratio of drug concentrations and as the relative infant dose (RID). Selective serotonin reuptake inhibitors were quantified by high-performance liquid chromatography combined with mass spectrometry. Results: Nineteen women treated with selective serotonin reuptake inhibitors during the third trimester of pregnancy and lactation were considered. Human milk-to-plasma ratios ranged from 51.1% to 703.4%. The patients had a median RID of 1.5%, with differences among the selective serotonin reuptake inhibitors. All newborns had been breastfed from birth up to day three of life. At 1 week follow up, 58% of infants were breastfed, 37% were complementary fed, and 5% were formula fed. No side effects due to passage of selective serotonin reuptake inhibitors into human milk were found. Conclusions: Selective serotonin reuptake inhibitors were detected in human milk, with milk-to-plasma ratios which in some cases exceeded 100%. Given the need for maternal therapy and the low incidence of neonatal adverse events, it is advisable not to preclude breastfeeding a priori but recommend it with careful follow-up.

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.

AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.