Intranasal bilosomes in thermosensitive hydrogel: advancing desvenlafaxine succinate delivery for depression management.

Depression, the second biggest cause of disability worldwide, is widespread. Many antidepressant medications, including Desvenlafaxine Succinate (D.V.S.), function by elevating neurotransmitter levels at the synapse through the inhibition of reabsorption by neurons. However, the effectiveness of these treatments is often limited by their inability to reach the brain using conventional administration methods. Bilosome-stabilized nanovesicles containing bile salts have drawn much interest because of their adaptability and versatility in various applications. This study aimed to address this issue by formulating intranasal bilosomes incorporated into a mucoadhesive in situ gel to deliver D.V.S. directly to the brain for depression treatment. The desvenlafaxine-loaded bilosomes were developed using a thin film hydration method based on the l-optimal design. They were intended to provide a more convenient route of administration for antidepressants, enhancing bioavailability and brain targeting through intranasal delivery. The study assessed the optimized bilosomes for particle size (311.21 ± 0.42 nm), Zeta potential (-37.35 ± 0.43)and encapsulation efficiency (99.53 ± 0.41%) and further evaluated them in ex vivo and in vivo pharmacokinetics studies. Pharmacokinetic data reveal enhanced brain uptake compared to a free drug. A statistically optimized bilosome formulation was determined. The intranasal administration of mucoadhesive in situ gel containing desvenlafaxine succinate-loaded bilosomes facilitated direct nose-to-brain drug delivery, improving brain bioavailability.

Predictors of functional response and remission with desvenlafaxine 50 mg and 100 mg: a pooled analysis of randomized, placebo-controlled studies in patients with major depressive disorder.

OBJECTIVE: The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo. METHODS: Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models. RESULTS: Functional early improvement thresholds of 17%-32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981-8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant. CONCLUSION: Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.

In Vitro-In Vivo Correlation for Desvenlafaxine Succinate Monohydrate Extended Release Tablets.

The objective of this study was to develop a dissolution test in order to establish an in vitro-in vivo correlation (IVIVC) model for desvenlafaxine succinate monohydrate (DVSM) extended release (ER) tablets. The in vitro release characteristics of the drug were determined using USP apparatus 1 at 75 rpm, with volume of HCl pH 1.2, acetate buffer solution (ABS) pH 4.5, or phosphate buffer solution (PBS) pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in healthy volunteers were obtained from a bioequivalence study. The similarity factors f1 and f2 were used to compare the dissolution data. The IVIVC model was developed using fraction dissolved and fraction absorbed of the reference product. For predictability, the results showed that the percentage prediction error (%PE) value of Cmax was 7.63%. The observed low prediction error for Cmax demonstrated that the IVIVC model was valid for this parameter.

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.

Categorical improvement in functional impairment in depressed patients treated with desvenlafaxine.

OBJECTIVE: This post-hoc pooled analysis evaluated categorical change in functional impairment in patients with major depressive disorder (MDD) treated with desvenlafaxine versus placebo and examined whether early improvement in functioning predicted functional outcomes at study endpoint. METHODS: Data were pooled from eight randomized, double-blind, placebo-controlled studies of desvenlafaxine for the treatment of MDD, including adults who were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo (N=3,384). Shift tables were generated for categorical changes in functional impairment from baseline based on Sheehan Disability Scale (SDS) subscale scores. The categories were none/mild (0-3), moderate (4-6), and marked/extreme (7-10). Treatment comparisons for prespecified shifts of interest and predictive value of week 2 or 4 improvement in SDS subscale scores for functional outcome at week 8 were assessed using logistic regression. RESULTS: Greater proportions of patients receiving desvenlafaxine 50 and 100 mg achieved improvement from baseline to week 8 for each prespecified shift endpoint versus placebo (all p ≤ 0.02). Early improvement in SDS subscale scores was a statistically significant predictor of functional outcome at week 8, both overall and for each treatment group (all p<0.0001). CONCLUSIONS: Treatment with desvenlafaxine 50 or 100 mg/d led to significantly greater categorical improvement in functional impairment versus placebo, and improvement in SDS subscale scores significantly predicted functional outcome. Monitoring patient progress early in the course of antidepressant treatment using a functional assessment such as the SDS may help clinicians determine whether or not treatment adjustments are needed.

Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials.

OBJECTIVE: Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective. METHODS: Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26. CONCLUSION: Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study.

BACKGROUND: Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. OBJECTIVE: To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. MATERIALS AND METHODS: A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. RESULTS: Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. CONCLUSION: Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Efficacy of Desvenlafaxine Compared With Placebo in Major Depressive Disorder Patients by Age Group and Severity of Depression at Baseline.

PURPOSE: This post hoc meta-analysis evaluated the efficacy and safety of desvenlafaxine 50 and 100 mg versus placebo across age groups and severity of depression at baseline in patients with major depressive disorder. METHODS: Data from placebo and desvenlafaxine 50-mg and 100-mg dose arms were pooled from 9 short-term, placebo-controlled, major depressive disorder studies (N = 4279). Effects of age (18-40 years, >40 to <55 years, 55-<65 years, and ≥65 years) and baseline depression severity (mild, 17-item Hamilton Rating Scale for Depression total score [HAM-D17] ≤18; moderate, HAM-D17 >18 to <25; severe, HAM-D17 ≥25) on desvenlafaxine efficacy were assessed using analysis of covariance for continuous end points and logistic regression for categorical end points. FINDINGS: Desvenlafaxine-treated (50 or 100 mg/d) patients had significantly (P < 0.05, 2-sided) greater improvement in most measures of depression and function compared with placebo for patients 18 to 40 years, older than 40 to younger than 55 years, and 55 to younger than 65 years, with no significant evidence of an effect of age. Desvenlafaxine significantly improved most measures of depression and function in moderately and severely depressed patients. There was a significant baseline severity by treatment interaction for HAM-D17 total score only (P = 0.027), with a larger treatment effect for the severely depressed group. IMPLICATIONS: Desvenlafaxine significantly improved depressive symptoms in patients younger than 65 years and in patients with moderate or severe baseline depression. Sample sizes were not adequate to assess desvenlafaxine efficacy in patients 65 years or older or with mild baseline depression.

Open-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjects.

BACKGROUND: Potential drugdrug interactions are a concern for patients taking tamoxifen. OBJECTIVE: This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. MATERIALS AND METHODS: This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUC(inf)), AUC to the last measurable concentration (AUC(last)), peak plasma concentration (C(max)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 - 125%. RESULTS: Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUC(inf), AUC(last), and C(max), as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUC(last) and C(max), respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). CONCLUSIONS: Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.

The association between antidepressant treatment and brain connectivity in two double-blind, placebo-controlled clinical trials: a treatment mechanism study.

BACKGROUND: Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies. METHODS: We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised). FINDINGS: Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: ß=-0·06; 95% CI -0·08 to -0·03; p<0·0001, ηp2=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, ηp2=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299). INTERPRETATION: The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics. FUNDING: National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.

Population Pharmacokinetics of Desvenlafaxine: Pharmacokinetics in Korean Versus US Populations.

Desvenlafaxine exposure in Korean and US populations was compared using population pharmacokinetic (PK) analysis. Data from a single- and multiple-dose study of desvenlafaxine (50, 100, and 200 mg) in 30 healthy Korean subjects were added to a population PK model previously developed using sparse PK samples from patients with major depressive disorder, including 140 Korean patients, combined with rich PK data from healthy volunteers. The structural PK model was an open 1-compartment linear disposition model with parallel first-order and 0-order inputs. The effects of Korean status on apparent oral clearance (CL/F) and apparent volume of distribution (V/F) were tested against the base model separately. External validation results indicated good agreement between the model predictions and observed desvenlafaxine concentrations for Korean subjects. The geometric mean CL/F and V/F of Korean subjects were 9.1% and 16.7% lower, respectively, than those of US subjects, who had a 20% higher mean body weight. Results for patients with major depressive disorder were similar. There were no meaningful differences for weight-normalized CL/F and V/F values between Korean and US subjects or patients. The minor differences in CL/F and V/F observed between Korean and US populations appear to be solely due to lower body weights in the Korean population.

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder.

OBJECTIVES: To evaluate the short-term efficacy and safety of desvenlafaxine (25-50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). METHODS: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. RESULTS: The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). CONCLUSION: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50 mg/d was generally safe and well tolerated in children and adolescents in this study.

Desvenlafaxine Versus Placebo in the Treatment of Children and Adolescents with Major Depressive Disorder.

OBJECTIVE: To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD). METHODS: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale. RESULTS: The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups. CONCLUSION: Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.

Clinical Experience With Desvenlafaxine in Treatment of Patients With Fibromyalgia Syndrome.

Two multicenter, randomized, placebo-controlled, adaptive-design trials of desvenlafaxine for fibromyalgia syndrome (FMS) were conducted. In study 1, male and female patients were randomized to a 27-week treatment with placebo or desvenlafaxine 50, 100, 200, or 400 mg/d. In study 2, female patients were randomized to an 8-week treatment with placebo, desvenlafaxine 200 mg/d, or pregabalin 450 mg/d after a placebo run-in. The primary efficacy end point was change from baseline in numeric rating scale (NRS) pain score. Protocol-specified interim analyses were planned after 12 (study 1) and 8 (study 2) weeks of treatment. Safety data were collected. In all, 697 patients were randomly assigned to treatment in study 1. At the interim analysis (n = 346), none of the desvenlafaxine doses met the efficacy criteria (mean [SE] advantage over placebo, -0.21 [0.36] to 0.04 [0.35]), and the study was terminated. Study 2 was stopped for business reasons before the planned interim analysis. NRS scores in week 8 were -1.98 (0.37), -1.60 (0.37), and -1.70 (0.38) for placebo (n = 26), desvenlafaxine 250 mg/d (n = 24), and pregabalin 450 mg/d (n = 21), respectively; neither active treatment differed significantly from placebo. Desvenlafaxine was generally safe and well tolerated. Efficacy of desvenlafaxine for pain associated with FMS was not demonstrated.

Effect of metabolic syndrome and thyroid hormone on efficacy of desvenlafaxine 50 and 100 mg/d in major depressive disorder.

OBJECTIVE: This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history. CLINICAL TRIAL REGISTRATION: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457. MAIN OUTCOME MEASURES: Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups-metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median-using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis. RESULTS: The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p > 0.05). LIMITATIONS: Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population). CONCLUSIONS: Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

OBJECTIVE: To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory. METHODS: The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents. CONCLUSIONS: Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation.

Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq(®), an extended release formulation (ERF). Semi-mechanistic models of desvenlafaxine were built (using SimCyp(®)) by combining in vitro data on dissolution and permeation (mechanistic part of model) with clinical data (obtained from literature) on distribution and clearance (non-mechanistic part of model). The model predictions of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus), respectively. Desvenlafaxine apparent permeability (Papp) at varying apical pH was investigated using the Caco-2 cell line and extrapolated to effective intestinal permeability (Peff) in human duodenum, jejunum, ileum and colon. Desvenlafaxine pKa-values and octanol-water partition coefficients (Do:w) were determined experimentally. Due to predicted rapid dissolution after IRF administration, desvenlafaxine was predicted to be available for permeation in the duodenum. Desvenlafaxine Do:w and Papp increased approximately 13-fold when increasing apical pH from 5.5 to 7.4. Desvenlafaxine Peff thus increased with pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low Peff in the upper small intestine, which "delays" the predicted time to the maximal plasma concentration (tmax), consistent with clinical data. Conversely, desvenlafaxine absorption from the ERF appears rate-limited by dissolution due to the formulation, which tends to negate the influence of pH-dependent permeability on absorption. We suggest that desvenlafaxine Peff is mainly driven by transcellular diffusion of the unionized form. In the case of desvenlafaxine, poor metabolism does not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability.

Comparison of efficacy, safety and brain derived neurotrophic factor (BDNF) levels in patients of major depressive disorder, treated with fluoxetine and desvenlafaxine.

This randomized, open label, prospective, observational study compared clinical efficacy, safety alongwith plasma BDNF levels in outpatients of depression treated with fluoxetine and desvenlafaxine. Patients (aged 18-60 years) with moderate to severe major depressive disorder (MDD) diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥14, who were prescribed fluoxetine or desvenlafaxine were included (n=30 in each group). Patients were followed up for 12 weeks for evaluation of clinical efficacy, safety along with BDNF levels. In the fluoxetine group, HAM-D scores at the start of treatment was 19±4.09 which significantly (p<0.05) reduced to 9.24±3.98 at 12 weeks. In the desvenlafaxine group, HAM-D scores at the start of treatment was 18±3.75 which significantly (p<0.05) reduced to 10±3.75 at 12 weeks. The BDNF levels in the fluoxetine group were 775.32±30.38pg/ml at the start of treatment which significantly (p<0.05) increased to 850.3±24.92pg/ml at 12 weeks. The BDNF levels in the desvenlafaxine group were 760.5±28.53pg/ml at the start of treatment which significantly (p<0.05) increased to 845.8±32.82pg/ml at 12 weeks. Both the antidepressants were found to be safe and well tolerated. The efficacy and the safety profile of desvenlafaxine is comparable to fluoxetine in patients of MDD. BDNF levels were significantly increased post-treatment with both the antidepressive agents. Whether BDNF may have a prognostic value in predicting treatment response to antidepressant drugs needs to be investigated in a larger patient population.

Effects of 50 and 100 mg desvenlafaxine versus placebo on sexual function in patients with major depressive disorder: a meta-analysis.

The primary objective of this post-hoc analysis was to evaluate the effect of short-term treatment with desvenlafaxine versus placebo on sexual dysfunction (SD), assessed from Arizona Sexual Experiences Scale scores, in adult outpatients with major depressive disorder. Data from three randomized, double-blind, placebo-controlled trials of 50 or 100 mg/day desvenlafaxine for major depressive disorder were pooled. SD status, determined from Arizona Sexual Experiences Scale scores, was assessed at baseline and week 8, last observation carried forward. Subgroup analyses addressed the effects of sex, baseline SD, and antidepressant response. At week 8, last observation carried forward (n=1562), SD rates were 54, 47, and 49% for 50 mg/day desvenlafaxine, 100 mg/day desvenlafaxine, and placebo, respectively [adjusted odds ratios (95% confidence interval) vs. placebo: 1.205 (0.928, 1.564) and 1.129 (0.795, 1.604), respectively]. The treatment by baseline SD interaction approached statistical significance (P=0.0663), mainly driven by poorer scores for desvenlafaxine versus placebo in the 100 mg group. Treatment by sex interactions were not statistically significant. Small but statistically significant treatment by sex interactions were observed for sex drive (P=0.0011) and ease of erection/lubrication (P=0.0151). Although there was no overall effect of desvenlafaxine on SD, a treatment by baseline SD interaction was suggested for 100 mg desvenlafaxine.