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Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.

Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.

Introduction Patients who take insomnia medication may change medications for reasons including lack of efficacy, adverse events, and dependence concerns. A pilot study (NCT04009577, E2006-A001-312) assessed a dosing approach for transitioning patients from zolpidem tartrate (ZOL; immediate or extended-release) to lemborexant, a dual orexin receptor antagonist. Here we describe characteristics of subjects who entered the study Screening Period and their reasons for wanting to change medications. Methods This multicenter pilot study was conducted in the U.S. and enrolled subjects age ≥18y with insomnia diagnosed per DSM-5 criteria, and who used ZOL (self-reported intermittently [3-4 nights/week] or frequently [≥5 nights/week]) as their only insomnia treatment. Subjects entered a 3-week Screening Period, during which frequency/dose of ZOL taken was recorded; subjects also wore an actigraph continuously. Eligible subjects thereafter entered the Treatment Phase to determine lemborexant dosing (5 or 10mg during a 2-week Titration Period with assignment to 1 of 3 treatment schedules based on ZOL usage frequency during Screening), followed by a 12-week Extension (Maintenance) Phase and a 4-week Follow-up Period. Results Forty-nine subjects entered the Screening period and completed the Chief Complaint Form through November 2019; mean(SD) age was 57.1(13.8)y, 67.3% were female, 69.4% were white, and 28.6% were black. 31 subjects reported using ZOL frequently and 15 reported using ZOL intermittently (3 missing). The most common sleep complaint was waking up too early (n=33), followed by difficulty staying asleep (n=13), and difficulty falling asleep (n=3). Reasons for wanting to switch from ZOL included: ZOL not working (n=19), concerns about taking ZOL (n=14), wanting to try something new/potentially better (n=6), side effects (n=5), and residual daytime sleepiness (n=4). 43/49 subjects completed screening through this period. Conclusion This study offers the opportunity to understand patients’ current use of insomnia medication and their motivation for wanting to change insomnia medications. Support Eisai Inc.

Introduction Switching of medications for insomnia occurs often in clinical practice based on a variety of reasons. However, few clinical studies have examined methods for transitioning patients between different insomnia medications. This is especially important to consider when the classes of drugs are different (e.g., GABA-ergic agonism vs orexin receptor antagonism); thus, clinical guidance would be valuable. The safety and efficacy of the dual orexin receptor antagonist lemborexant (LEM) for the treatment of insomnia was confirmed in two Phase 3 studies, SUNRISE-1 (NCT02783729, E2006-G000-304) and SUNRISE-2 (NCT02952820, E2006-G000-303). This pilot study (NCT04009577, E2006-A001-312) was designed to assess pre-specified dosing approaches for directly transitioning from the sedative-hypnotic zolpidem (ZOL), a commonly prescribed sleep aid, to LEM. Methods This multicenter pilot study has enrolled subjects age ≥18 years with an insomnia diagnosis (DSM-5 criteria), who used ZOL (intermittently or frequently) as their only insomnia treatment. Following a 3-week Screening period, eligible subjects enter the Treatment Phase (2-week titration period: assigned to 1 of 3 treatment arms based on ZOL use during Screening), and then the Extension Phase (maintenance period up to 12 weeks). During both the Treatment and Extension Phases, the dose of LEM is flexible between 5 and 10 mg, depending on efficacy and tolerability. The primary endpoint is to evaluate the proportion of subjects taking ZOL who successfully transition to LEM (lemborexant 5 mg [LEM5] or lemborexant 10 mg [LEM10]) after 2 weeks of LEM treatment. Results Enrollment began July 15, 2019. It was initially projected that approximately 110 subjects would be screened to provide about 60 subjects for randomization across 3 treatment arms. Interim data will be presented (planned cutoff date Jan 08, 2020). Conclusion This pilot study will help inform on dosing guidance when transitioning a patient from a GABA-ergic drug to an orexin receptor antagonist. Support Eisai Inc.

Venlafaxine is a clinically effective antidepressant. Caffeine is a metabolic probe for the quantitative measurement of CYP1A2 activity in vivo. This open-label study evaluated the effect of steady-state venlafaxine on CYP1A2-dependent metabolism, as measured by the pharmacokinetic disposition of caffeine, and urinary caffeine metabolite ratios (CMRs). Sixteen healthy subjects received 200 mg of caffeine orally before (Day 1) and after (Day 8) venlafaxine was titrated to steady-state (37. 5 mg every 12 hours on Days 2-4, then 75 mg every 12 hours on Days 5-8). Samples were collected before and for 24 hours after caffeine dosing for the determination of caffeine in plasma and 1,7-dimethylxanthine, 3,7-dimethylxanthine, 1,7-dimethyluric acid (17U), 1-methylxanthine (1X) and 1-methyluric acid (1U), and 5-acetylamino-6-amino-3-methyluracil (AAMU) in urine. Blood samples were obtained before venlafaxine doses on Days 7 and 8 (morning dose only) for the determination of trough venlafaxine and O-desmethylvenlafaxine levels. Venlafaxine did not significantly alter the pharmacokinetics of caffeine and its metabolites. Plasma caffeine AUC was unchanged and remained within the bioequivalence criteria (90% confidence interval: 87.9%-102%) in the presence of venlafaxine. Urine metabolite data showed variable increases and decreases in the CMR [(AAMU + 1 U + 1X)/17U] for individual subjects. However, the mean CMR was altered by < 10% in the presence of venlafaxine. This in viva study demonstrated that venlafaxine did not alter the pharmacokinetic profile of caffeine and confirms in vitro data that venlafaxine does not inhibit CYP1A2 metabolism. Therefore, venlafaxine appears to have a relatively low potential for drug interactions based on CYP1A2 inhibition.

An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risperidone before and after venlafaxine dosing to steady state. No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety. However, venlafaxine weakly altered the pharmacokinetics of risperidone. Oral clearance decreased 38%, and the volume of distribution decreased 17%, resulting in a 32% increase in the AUC for risperidone. Renal clearance of 9-hydroxyrisperidone also decreased by 20% in the presence of venlafaxine. Safety profiles of both drugs were not altered. This study demonstrated that venlafaxine did not affect the pharmacokinetic profile of 9-hydroxyrisperidone or the total active moiety, although it weakly inhibited the metabolism of risperidone. These results show that venlafaxine is unlikely to be involved in a pharmacokinetic interaction with concomitant risperidone.

Psychotropic drug dosing regimens are often based on the pharmacokinetic elimination half-life of the compound. This implies that the pharmacokinetic half-life of the drug may be the critical or sole determinant of pharmacodynamic half-life. In the present study, we examined the safety and efficacy of once- versus twice-daily dosing regimens of the immediate-release formulation of venlafaxine, a serotonin and norepinephrine reuptake site blocker with a short elimination half-life.Forty-eight patients with a diagnosis of DSM-IV major depressive episode were randomly assigned to once-daily (N = 25) versus twice-daily (N = 23) venlafaxine. Venlafaxine was started at 37.5 mg daily with specified increments up to 225 mg daily. Efficacy was rated using the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale (CGI).Twenty-one patients in each group completed 6 weeks of treatment. We observed a significant reduction in mean weekly HAM-D and MADRS scores at weeks 1 through 6 for both dosing groups (p.001). There were no statistically significant differences in mean HAM-D or MADRS scores between dosing groups at any time point. There was, however, a nonsignificant trend for a more rapid reduction in the mean HAM-D score at week 2 (p.06) and in the mean MADRS score at week 1 (p.07) and week 2 (p.09) in the b.i.d. dosing group. Similarly, there was a significant decrease in the CGI score at week 2 (p.02) in the b.i.d. dosing group. The rate of adverse events was similar between treatment groups; the most common adverse events were transient nausea and headaches.These results indicate that the immediate-release formulation of venlafaxine may be safe and effective in some patients when used in a once-daily dose regimen. Moreover, the present results suggest that the short elimination half-life of immediate-release venlafaxine should not be the sole determinant for multiple daily dosing and that antidepressant activity may be more profoundly influenced by a drug's pharmacodynamic half-life than by its pharmacokinetic half-life.

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.