Serum Concentrations Of Venlafaxine Research Articles

Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis

IntroductionRecent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose. Patients and methodsRetrospective study carried out in the Balearic Islands (2020–2023). Inclusion criteria: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared. ResultsTwenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459–17,976] in patients with hypoglycemia and 1,413 [930–1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05). ConclusionsThe detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication.

The Influence of Combined CYP2D6 and CYP2C19 Genotypes on Venlafaxine and O-Desmethylvenlafaxine Concentrations in a Large Patient Cohort.

The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population. Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference. The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%. The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.

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.

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. 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. 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. 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.

Reduced clearance of venlafaxine in a combined treatment with quetiapine

Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet.A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V0 (n = 153) and co-medication with quetiapine, VQUE (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype.The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co-medicated group.Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine.

Effects of Proton Pump Inhibitors (PPI) on the serum concentrations of Venlafaxine

Objectives: Venlafaxine is metabolized by CYP2D6 to O-desmethylvenlafaxine (ODV) and by CYP3A4 to N-desmethylvenlafaxine (NDV). CYP2C19 is also involved in the formation of ODV. The PPIs omeprazole and pantoprazole inhibit CYP2C19 to a different extent. Aim of this study was to investigate the potential effects of both PPIs on serum levels of VEN and ODV. Methods: From a therapeutic drug monitoring (TDM) database, serum concentrations of VEN, ODV and the active moiety (VEN + ODV), were analyzed. Data from 120 patients were available and splitted into three groups: patients without PPI [noPPI], with pantoprazole [PANTO] or with omeprazole [OMEP] (n = 40 each). The ratio of (ODV/VEN) was calculated as a marker of the metabolizer status. For statistical comparison the Studentʼs t-test was used. Results: Differences in the ratio ODV/VEN were neither found between the PANTO and OMEP group (p = 0.659), nor between the noPPI group and the PPI groups (OMEP: p = 0.196; PANTO: p = 0.107). However, both PPI groups showed elevated levels of VEN compared with the noPPI group, OMEP (p = 0.037), PANTO (p = 0.042). Values of the active moiety were significantly higher in the OMEP group (p = 0.044). Conclusion: Both, omeprazole and pantoprazole led to a varying extent in increases of the serum concentrations of venlafaxine. The increase is driven by significantly higher levels of VEN rather than by increasing levels of ODV. This might be due to CYP2C19 blocking properties of both PPIs.

Steady-state serum concentrations of venlafaxine in patients with late-life depression. Impact of age, sex and BMI.

Diagnosis of late-life depression is given when depressive symptoms emerge in persons older than 65 years. Great care is needed when elderly patients receive psychopharmacotherapy due to altered pharmacokinetic status. As a consequence, age is considered to have a significant effect on serum concentrations of antidepressant drugs. The magnitudes of age-dependent changes, however, are uncertain. By utilizing a large therapeutic drug monitoring (TDM) database, this cross-sectional study aimed to retrospectively assess pharmacotherapy in elderly patients in comparison with their younger counterparts, when treated with venlafaxine, which is widely used to treat late-life depression. In addition, the influence of sex and body mass index (BMI) was evaluated. Serum concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine requested during routine TDM in two University Medical Centers in Germany were analyzed. Patients with concomitant CYP2D6 inhibiting drugs as co-medication were excluded. In total, 1,417 samples were available for the analysis. Elderly patients had by average 42% higher dose-adjusted serum concentrations (ng/mL/mg) of the active moiety (venlafaxine plus O-desmethylvenlafaxine) than younger patients. In addition, our study demonstrated that the difference between age groups is independent of sex and BMI. However, age groups only explain 4.5% of the total dose-adjusted serum concentration variation of the venlafaxine active moiety. Dose adjustments for venlafaxine are recommended in patients aged 65 years or older, particularly in elderly female patients who are exceptionally vulnerable to high serum concentrations of venlafaxine. TDM is recommended during venlafaxine pharmacotherapy.

Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups.

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups. Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40-65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses. In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups). This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

Severe Tremor After Cotrimoxazole-Induced Elevation of Venlafaxine Serum Concentrations in a Patient With Major Depressive Disorder

: We describe a female patient who was an extensive metabolizer of cytochrome P450 isoenzyme (CYP) 2D6 and an intermediate metabolizer of CYP2C19 (genotype: CYP2C19 *1/*2). She exhibited high serum concentrations of venlafaxine and O-desmethylvenlafaxine and developed severe tremor after comedication with cotrimoxazole (sulfamethazole/trimethoprim). Venlafaxine is mainly metabolized by O- and N-demethylation. O-demethylation is catalyzed by the highly polymorphic CYP2D6 and N-demethylation by several enzymes, CYP2C19, CYP2C9, and CYP3A4. The observed overall pharmacokinetic effect was most probably the result of decreased N-demethylation of venlafaxine by (1) reduced expression of CYP2C19 due to a genetic deficit and (2) inhibition of CYP2C9 by cotrimoxazole.

Additive effects of sex, age and smoking on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions

Introduction: Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of sex, age and smoking on serum concentrations of VEN, its metabolite O-desmethylvenlafaxine (ODVEN) and the sum of both (SUM) in patients treated with VEN under naturalistic conditions. Methods: We retrospectively evaluated therapeutic drug monitoring (TDM) analyses of VEN in 234 patients treated in the psychiatric university hospitals of Mainz, Regensburg, and Wurzburg for a depressive episode (ICD-10 F3x). The determination of serum concentrations was performed by virtually identical chromatographic methods in the therapeutic drug monitoring (TDM) laboratories of the participating hospitals. Results: Serum concentrations varied widely depending on the variables sex, age and smoking. Although there was no significant difference between the 8 groups (smokers vs. non-smokers x males vs. females x ≤ 60 years vs. > 60 years) regarding daily dose and venlafaxine serum concentration, smoking males ≤ 60 years (n = 15) had a mean serum concentration of ODVEN and SUM of 150.40 ng/ml (SD 77.86) and 251.00 ng/ml (SD 106.65), which is less than half of serum concentrations of non-smoking females > 60 years (n = 26, ODVEN mean 309.08 ng/ml, SD 195.11 and SUM mean 508.04 ng/ml, SD 268.03). An ANOVA over the 8 different groups is significant for ODVEN (p < 0.028) and SUM (p < 0.011). Discussion: Variables like sex, age and smoking should be considered for optimal dosing of patients with VEN. There seems to be an additive effect of these variables regarding their influence on the serum concentrations of VEN that can lead to a greater risk of under- or overdosage of VEN.

Maternal Use of Venlafaxine Near Term: Correlation Between Neonatal Effects and Plasma Concentrations

The nature of neonatal adverse effects in the offspring after maternal use of venlafaxine at term is not fully understood. We correlated neonatal clinical signs over time with serum concentrations of venlafaxine and its active metabolite in the neonatal period. Women exposed to venlafaxine near term, and their neonates, were studied. Adverse neonatal signs and serum concentrations of venlafaxine and its active metabolite were assessed. Seven mother-child pairs were studied. Median maternal venlafaxine dose was 75 mg/d (37.5-300 mg/d). Five neonates presented with multiple clinical signs during their hospital stay, all including tachypnea and respiratory distress. Respiratory distress was present within the first hours after birth, with other symptoms appearing subsequently when the drug concentration declined. The elimination half-life, calculated for 3 neonates, ranged between 12 and 15 hours for venlafaxine and between 10 and 37 hours for O-desmethylvenlafaxine. Neonatal clinical signs emerged as drug concentrations declined, corroborating discontinuation as an etiology. Respiratory symptoms tended to occur earlier and, in one case, independently from the typical signs of abrupt cessation of venlafaxine. This suggests that it may be part of the wide range of respiratory problems reported in antidepressant-exposed neonates, including persistent pulmonary hypertension of the newborn reported with selective serotonin reuptake inhibitor. Neonatal clinical signs emerged with decreasing concentrations of venlafaxine, supporting that abrupt cessation of venlafaxine leads to discontinuation syndrome. Respiratory problems occurred earlier than typical discontinuation clinical signs. Larger studies are needed to confirm these findings.

Rapid and reliable genotyping procedure for detection of alleles with mutations, deletion, or/and duplication of the CYP2D6 gene

Background Polymorphisms of cytochrome P450 2D6 (CYP2D6) have a significant effect on the pharmacokinetics of most tricyclic antidepressants. More than 150 alleles lead to four distinct phenotypes of drug metabolism. The phenotypes are described as ultrarapid, extensive, intermediate, and poor metabolizers. Therapeutic plasma levels of CYP2D6 substrates may be difficult to achieve. Here we describe a rapid and reliable procedure for CYP2D6*4, *3, *6, and *9 genotyping. Design and methods Serum concentrations of venlafaxine and its pharmacologically active metabolite, O-desmethylvenlafaxine, were measured in patients treated with the antidepressant venlafaxine, a substrate of CYP2D6. The ODV/V ratio was used as an indicator of the CYP2D6 phenotype, with a higher ratio reflecting more rapid metabolism. Real-time PCR with fluorometric melting point analysis of the PCR products (LightCycler ®) is used to identify SNPs. Using quantitative PCR, gene deletion and gene duplication or multiplication are investigated by measurement of the fluorescence intensity quotient ( q, N) of the CYP2D6 gene relative to that of the albumin gene as an internal standard. Results Melting curves are verified using DNA samples of known genotypes and by sequencing the PCR products. The genotypes and phenotypes that were detected correspond to each other. Conclusion A PCR procedure for the detection of CYP2D6 SNPs, deletions, and duplications is described and is rapid and reliable.

Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele

Increased systemic exposure of the antidepressant venlafaxine and increased risk of side effects has previously been observed in patients with defective CYP2D6 function [poor metabolisers (PMs)]. The aim of this study was to evaluate venlafaxine pharmacokinetics in carriers of one functional and one defective CYP2D6 allele [heterozygous extensive metabolisers (HEMs)]. Data was collected retrospectively from a therapeutic drug-monitoring database. All CYP-genotyped patients with steady-state serum concentration measurements of venlafaxine and metabolites were included in the study. Patients were divided in groups: *1/*1 [homozygous extensive metabolisers (EMs)], *1/*3, *4 or *5 (HEMs) and *4/*4 (PMs). Dose-adjusted serum concentrations of venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, and the metabolic ratio (O-desmethylvenlafaxine/venlafaxine) were compared between the different genotype groups. The sum of venlafaxine and O-desmethylvenlafaxine serum concentrations was not significantly different between genotype groups. Metabolic ratio was 50% lower in HEMs (n = 18) than in EMs (n = 20) (p < 0.05). Serum concentration of N-desmethylvenlafaxine was 5.5-fold higher in HEMs (p < 0.01) and 22-fold higher in PMs (p < 0.001) than in EMs. The study showed a shift in the metabolic pathway resulting in substantially higher levels of N-desmethylvenlafaxine in HEMs than in EMs. The metabolic pattern of venlafaxine in HEMs was similar to previous observations in PMs and possibly represents an increased risk of venlafaxine-related side effects in HEM patients.

Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine.

Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly and the serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. Patients treated concomitantly with venlafaxine and melperone had significantly higher (mean +/- SD) venlafaxine (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylvenlafaxine serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, venlafaxine serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylvenlafaxine was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). This study pointed to an inhibitory effect of melperone on the O-demethylation of venlafaxine. Because the O-demethylation of venlafaxine is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.