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.

Planned complex suicide involving combined drug intoxication and femoral catheterization.

Complex planned suicide is characterized by the simultaneous use of two or more methods to ensure that death occurs even if one method fails. The authors present an original combination of two self-killing methods. A 42-year-old cardiologist, with a major depressive syndrome and several suicide attempts, as well as cocaine addiction, was found dead at his home with a femoral catheter inserted in the right femoral artery. The autopsy concluded that death was due to major hemorrhagic process in a context of suicide. Toxicological analyses, performed in peripheral blood by gas chromatography coupled to mass spectrometry and by liquid chromatography-diode array detection, revealed the presence of ethanol (0.13 g/L), cocaine, and metabolites (cocaine: 432 µg/L, benzoylecgonine: 3286 µg/L, ecgonine methyl ester: 1195 µg/L, cocaethylene: 41 µg/L), a potentially lethal concentration of citalopram (1.03 mg/L), toxic concentrations of hydroxyzine (0.11 mg/L), bromazepam (2.06 mg/L), and lidocaine (7.30 mg/L). At the end of these analyses, the death was reclassified as planned complex suicide combining drug intoxication and catheterization of the femoral artery. The authors discuss the main aspects of this case and stress the importance of meticulous analysis of all available evidence: witness reports, victim's medical history and occupation, findings of at-the-scene examination, autopsy, and toxicological analyses, in order to exclude homicide and to understand the sequence of events that led to death.

Subtherapeutic bupropion and hydroxybupropion serum concentrations in a patient with CYP2C19*1/*17 genotype suggesting a rapid metabolizer status.

Bupropion is hydroxylated to its primary active metabolite hydroxybupropion by cytochrome P450 enzyme CYP2B6. In vitro data suggest the existence of alternative hydroxylation pathways mediated by the highly polymorphic enzyme CYP2C19. However, the impact of its genetic variants on bupropion metabolism in vivo is still under investigation. We report the case of a 28-year-old male Caucasian outpatient suffering from major depressive disorder who did not respond to a treatment with bupropion. Therapeutic drug monitoring revealed very low serum concentrations of both bupropion and hydroxybupropion. Genotyping identified a heterozygous status for the gain-of-function allele with the genotype CYP2C19*1/*17 predicting enhanced enzymatic activity. The present case shows a reduced bupropion efficacy, which may be explained by a reduced active moiety of bupropion and its active metabolite hydroxybupropion, due to alternative hydroxylation pathways mediated by CYP2C19 in an individual with CYP2C19 rapid metabolizer status. The case report thus illustrates the clinical relevance of therapeutic drug monitoring in combination with pharmacogenetics diagnostics for a personalized treatment approach.

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.

Development of HPLC method coupled with fluorescence detection for simultaneous determination of donepezil HCl and trazodone HCl in spiked human plasma and tablets dosage forms.

OBJECTIVES: Elderly people with dementia are commonly suffered from sleep disorders. So, the use of Donepezil hydrochloride as anti-Alzheimer drug and Trazodone hydrochloride as antidepressants with hypnotic action is very important in these cases. This study reports about novel and sensitive RP-HPLC method with fluorescence detection for simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and co-administered, Trazodone hydrochloride (TRA) in their pure forms, spiked human plasma and tablets. MATERIALS AND METHODS: Elution of both drugs was achieved with excellent resolution using a RP-C18 Hypersil Gold column and an isocratic mobile phase consisting of phosphate buffer (50mm, pH 4.6): methanol: acetonitrile (60:35:5) with a flow rate of 1.5mL/min and 20µL as injection volume. A Fluorescence detector at 300nm for excitation and 400nm for emission was used. RESULTS: Retention times were 4.3 and 6.3min for Donepezil hydrochloride and Trazodone hydrochloride, respectively. Linearity ranges of the assay were 25-1000 and 50-5000ng/mL and the limits of detection (LOD) and quantitation (LOQ) were 8.52, 15.47 and 25.81, 46.89ng/mL for Donepezil hydrochloride and Trazodone hydrochloride, respectively. CONCLUSION: The high sensitivity of the proposed method enabled the successful determination of the cited drugs in spiked human plasma with mean percentage of recoveries of 91.58±3.34 and 100.30±5.11 for Donepezil hydrochloride and Trazodone hydrochloride, respectively.

Pharmacokinetic correlates of venlafaxine: associated adverse reactions.

To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.

Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes.

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.

Development of a fluvoxamine detection system using a Quenchbody, a novel fluorescent biosensor.

The misuse of psychotropic drugs intended for medical treatment represents a recent worldwide public health concern. Quenchbody (Q-body) is a novel fluoroimmunosensor that can detect an antigen immediately without additional reagents or washing steps. Here, we describe creating Q-bodies for the detection of the antidepressant fluvoxamine (FLV) and determining optimal conditions to achieve the highest fluorescence intensity (FI). We prepared five Q-bodies with the fluorophore labeled at either the N- or C- terminus and with different linker lengths. Fluorescence was measurable within minutes, indicating the interaction of Q-bodies with FLV. The normalized FI (FI ratio) of the N-terminus labeled Q-body increased approximately 1.5-fold upon FLV addition; Q-bodies labeled at the C-terminus did not significantly increase FI. Among the fluorescence dyes used in this study, Rhodamine 6G labeled Q-body showed the best FI ratio. EC50 values of the N-terminus labeled Q-bodies were similar (23.2-224nM) regardless of linker length or labeling dye. We examined whether the Q-body could be applicable to serum matrix instead of phosphate-buffered saline. The intact serum interfered strongly with the Q-body fluorescence. However, the FI ratios of the Q-body for FLV-spiked serum filtrate, for which proteins were removed by filtration, showed a dose-dependency for detecting FLV levels. Deproteinization, which does not interfere with Q-body fluorescence measurements, is likely necessary to detect serum FLV with high sensitivity. This study demonstrates the potential of Q-body probes as a tool towards developing creative immunoassay applications.

Development of bioanalytical HPLC method for simultaneous determination of the antialzhiemer, donepezil hydrochloride and the antidepressant, citalopram hydrobromide in raw materials, spiked human plasma and tablets dosage form.

OBJECTIVES: A novel, fast and sensitive HPLC method has been developed for the simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and Citalopram hydrobromide (CTP) in raw materials, spiked human plasma and tablets. MATERIALS AND METHODS: Elution of both drugs was achieved with very good resolution using a RP-C18 chromatographic column, samples were analyzed using Hypersil Gold (100mm×4.6mm), 5µm particle size column and an isocratic binary mobile phase consists of phosphate buffer (0.05 M): acetonitrile (65:35). A Diode array detector at wavelength 232nm was used. Chromatographic separation was within a short run time (less than 7minutes) for both drugs. RESULTS: Retention times for DON and CTP were 4.5 and 5.8min, respectively. Linear calibration curves were obtained for DON and CTP over the concentration ranges of 0.1-10 and 0.1-50µg/mL. The mean extraction recoveries from spiked plasma were 93.22 and 92.64 for DON and CTP, respectively. The limits of detection and quantification were 0.017, 0.035µg/mL and 0.052, 0.106µg/mL for DON and CTP, respectively. CONCLUSION: The proposed method was successfully applied to the analysis of the cited drugs in raw materials, spiked human plasma and tablets with excellent accuracy and precision.

Degradation of Bupropion: Implications for Interpretation of Postmortem Case Data.

The interpretation of postmortem bupropion is often a challenge to the forensic toxicology community because of the instability of the parent compound. At the North Carolina Office of the Chief Medical Examiner (NC OCME) toxicology laboratory, one of the active metabolites, threobupropion, is used as a complementary indicator for the extent of exposure to the parent compound. Metabolite data will address postmortem normal concentrations as well as when bupropion was attributed to the cause of death. For 55 natural cases where bupropion was unattributed to the cause of death, the blood and liver mean threobupropion concentrations were 1.8 mg/L and 12.1 mg/kg, respectively, with median concentrations of 1.5 mg/L and 10 mg/kg, respectively. For the 51 suicidal ingestion cases when bupropion was attributed to the cause of death, the blood and liver mean threobupropion concentrations were 15.8 mg/L and 131.5 mg/kg, respectively, with median concentrations of 13.5 mg/L and 110 mg/kg, respectively. The laboratory completed a stability study over the course of 50 days to evaluate how bupropion and threobupropion degrade in postmortem blood, liver and liver homogenate. The samples were subjected to forensically relevant conditions by storing them at room temperature (RT, 20°C), refrigerated (4°C) and frozen (-20°C). While the concentration of bupropion decreased in all specimens, the rate of degradation of the RT samples was the most dramatic. The threobupropion metabolite appeared to be relatively stable. The postmortem case data along with the evaluation of potential degradation products should provide an overall picture to assist the toxicological community with the interpretation of bupropion found in routine casework.

Effects of Magnesium Supplementation on Unipolar Depression: A Placebo-Controlled Study and Review of the Importance of Dosing and Magnesium Status in the Therapeutic Response.

Animal studies using tests and models have demonstrated that magnesium exerts an antidepressant effect. The literature contains few studies in humans involving attempts to augment antidepressant therapy with magnesium ions. The purpose of our study was to assess the efficacy and safety of antidepressant treatment, in combination with magnesium ions. A total of 37 participants with recurrent depressive disorder who developed a depressive episode were included in this study. As part of this double-blind study, treatment with the antidepressant fluoxetine was accompanied with either magnesium ions (120 mg/day as magnesium aspartate) or placebo. During an 8-week treatment period, each patient was monitored for any clinical abnormalities. Moreover, serum fluoxetine and magnesium levels were measured, and pharmaco-electroencephalography was performed. The fluoxetine + magnesium and fluoxetine + placebo groups showed no significant differences in either Hamilton Depression Rating Scale (HDRS) scores or serum magnesium levels at any stage of treatment. Multivariate statistical analysis of the whole investigated group showed that the following parameters increased the odds of effective treatment: lower baseline HDRS scores, female gender, smoking, and treatment augmentation with magnesium. The parameters that increased the odds of remission were lower baseline HDRS scores, shorter history of disease, the presence of antidepressant-induced changes in the pharmaco-EEG profile at 6 h after treatment, and the fact of receiving treatment augmented with magnesium ions. The limitation of this study is a small sample size.

Venlafaxine Determination in Pharmaceutical Formulation and Serum by Ion-Selective Electrodes.

BACKGROUND: The application of an ion selective technique for the determination of analyte concentrations is considered one of the most economical techniques for quality control purposes. OBJECTIVE: To elaborate and investigate the construction and general performance characteristics of potentiometric PVC membrane sensors for venlafaxine cation (Ven+). METHOD: The sensors are based on the use of the ion association complexes of the venlafaxine cation with phosphotungstate (PT) and silicotungstate (ST) counter anions as ion exchange sites in the plasticized PVC matrix. They are characterized by potentiometric and conductimetric measurements, performed under various conditions. RESULTS: The electrodes showed a fast (response time around 15 s), stable (life span 45 days) and linear (r2 0.995) response for venlafaxine over the concentration range of 5x10-5 - 1x10-2 M venlafaxine hydrochloride. The solubility product of the ion pair and the formation of the precipitation reaction leading to the ion pair, were determined conductimetrically. The electrodes were found to be very selective, precise (RSD < 1%) and applicable to the potentiometric determination of venlafaxine hydrochloride in pure solutions or in pharmaceutical preparation and in biological fluid (serum), without any interference. Validation of the method shows the suitability of the proposed electrodes for use in the quality assessment of venlafaxine hydrochloride. CONCLUSION: Using only a pH meter in combination with the selective electrodes, drug substance or drug product could be determined accurately in a few seconds. In addition, the in-house made electrodes were tested to monitor venlafaxine in serum. Acceptable results were achieved using the standard addition technique.

Serum and Saliva Concentrations of Venlafaxine, O-Desmethylvenlafaxine, Quetiapine, and Citalopram in Psychiatric Patients.

BACKGROUND: Therapeutic drug monitoring has become increasingly important in psychiatric therapy. However, it is not yet implemented as a daily routine in clinical settings. To evaluate new, noninvasive procedures, we compared blood and saliva venlafaxine, quetiapine, and citalopram concentrations in samples collected from psychiatric patients. METHODS: We collected blood and saliva samples from 75 psychiatric patients (39 venlafaxine, 19 quetiapine, and 17 citalopram). Saliva sampling was achieved by the use of cotton pads. Venlafaxine (and its metabolite O-desmethylvenlafaxine) and quetiapine were analyzed by LC-MS/MS, whereas citalopram was analyzed by HPLC. RESULTS: We observed significant correlations between concentrations of venlafaxine (ratio saliva/serum ± SD: 18.3 ± 9.5, P < 0.01, r = 0.895) and its metabolite O-desmethylvenlafaxine (ratio saliva/serum ± SD: 4.1 ± 3.2, P < 0.05, r = 0.344), quetiapine (ratio saliva/serum ± SD: 0.2 ± 0.2, P < 0.01, r = 0.935), and citalopram (ratio saliva/serum ± SD: 2.6 ± 1.2, P < 0.05, r = 0.54) in serum and in saliva. Furthermore, measured concentrations of venlafaxine (and its metabolite O-desmethylvenlafaxine) and citalopram were higher in saliva than in serum, whereas measured concentrations of quetiapine were higher in serum than in saliva. CONCLUSIONS: Using cotton pad saliva sampling, venlafaxine and quetiapine demonstrate high correlations between saliva and serum concentrations, whereas for O-desmethylvenlafaxine and citalopram, other methods of sampling might be preferable. Saliva therapeutic drug monitoring of psychoactive drugs might become a useful approach to achieving individual treatment regimens.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02438072.

Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism.

BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording.

Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine.

BACKGROUND AND OBJECTIVE: An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug-drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs-omeprazole and pantoprazole-and venlafaxine. METHODS: A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40). Plasma concentrations of venlafaxine, O-desmethylvenlafaxine and active moiety (venlafaxine + O-desmethylvenlafaxine), as well as dose-adjusted plasma concentrations, were compared using non-parametrical tests. RESULTS: Daily doses of venlafaxine did not differ between groups (p = 0.949). The Mann-Whitney U test showed significantly higher plasma concentrations of active moiety, as well as venlafaxine and O-desmethylvenlafaxine, in both PPI groups [p = 0.023, p = 0.011, p = 0.026, +29% active moiety, +27% venlafaxine, +36% O-desmethylvenlafaxine (pantoprazole); p = 0.003, p = 0.039 and p < 0.001, +36% active moiety, +27% venlafaxine, +55% O-desmethylvenlafaxine (omeprazole)]. Significantly higher concentration-by-dose (C/D) values for venlafaxine and active moiety were detected in the pantoprazole group (p = 0.013, p = 0.006, respectively), while in the omeprazole group, C/D ratios for all three parameters-venlafaxine, O-desmethylvenlafaxine and active moiety-were significantly higher (p = 0.021, p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Significantly higher plasma concentrations for all parameters (venlafaxine, O-desmethylvenlafaxine, active moiety) suggest clinically relevant inhibitory effects of both PPIs, most likely on the cytochrome P450 (CYP) 2C19-mediated metabolism of venlafaxine. The findings might be the result of different degrees of CYP2C19 involvement, therefore the inhibition of CYP2C19 by both PPIs may lead to an increased metabolism via CYP2D6 to O-desmethylvenlafaxine.

Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study).

BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. METHODS/DESIGN: This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. DISCUSSION: By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Escitalopram plasma levels and antidepressant response.

Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (p<0.001) and month 3 (p=0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE-SCE2) explained a higher proportion of variance compared to the linear other models (p<0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings.