Adverse Events and Measurement of Dissociation After the First Dose of Esketamine in Patients With TRD.

BACKGROUND: "Dissociation" comprises distinct phenomena, some of which are associated with esketamine treatment and some may overlap with positive symptoms of psychosis. Relationships between dissociation and psychotic symptoms assessed by -clinician report vs conventional rating scales were investigated in a post hoc analysis of data from the initial treatment session in an -open-label, -long-term safety, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression. METHODS: Adverse events of dissociation or psychosis were examined via investigator report and the Clinician Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale-Plus, respectively, 40 minutes post first esketamine dose. The range of CADSS total scores associated with investigator-reported severity of dissociation was determined by equipercentile linking. Logistic regression models and receiver operating curve analysis explored the CADSS cutoff point for determining presence/absence of dissociation. Frequency of response to specific CADSS items was examined to investigate qualitative differences in the pattern of symptoms reported across investigator-reported levels of adverse event severity. RESULTS: Dissociation was reported as an adverse event in 14.3% (109/764) of patients. Severity of most CADSS items increased with the severity of investigator-reported dissociation. No CADSS cutoff point discriminated well between the presence and absence of dissociation events. Hallucinations were reported as adverse events in 5 patients; none reported delusions. CONCLUSIONS: CADSS scores and severity of dissociation adverse events move generally in the same direction; however, there is substantial variability in this relationship. No signature profile of dissociative experiences was revealed, and psychotic symptoms were uncommon. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02497287.

Montgomery-Åsberg Depression Rating Scale factors in treatment-resistant depression at onset of treatment: Derivation, replication, and change over time during treatment with esketamine.

OBJECTIVE: Derive and confirm factor structure of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with treatment-resistant depression (TRD) and evaluate how the factors evident at baseline change over 4 weeks of esketamine treatment. METHODS: Two similarly-designed, short-term TRANSFORM trials randomized adults to esketamine or matching placebo nasal spray, each with a newly-initiated oral antidepressant, for 4 weeks (TRANSFORM-1: N = 342 patients; TRANSFORM-2: N = 223 patients). The factor structure of MADRS item scores at baseline was determined by exploratory factor analysis in TRANSFORM-2 and corroborated by confirmatory factor analysis in TRANSFORM-1. Change in MADRS factor scores from baseline (day 1) to the end of the 28-day double-blind treatment phase of TRANSFORM-2 was analyzed using a mixed-effects model for repeated measures (MMRM). RESULTS: Three factors were identified based on analysis of MADRS items: Factor 1 labeled affective and anhedonic symptoms (apparent sadness, reported sadness, lassitude, inability to feel), Factor 2 labeled anxiety and vegetative symptoms (inner tension, reduced sleep, reduced appetite, concentration difficulties), and Factor 3 labeled hopelessness (pessimistic thoughts, suicidal thoughts). The three-factor structure observed in TRANSFORM-2 was verified in TRANSFORM-1. Treatment benefit at 24 h with esketamine versus placebo was observed on all 3 factors and continued throughout the 4-week double-blind treatment period. CONCLUSIONS: A three-factor structure for MADRS appears to generalize to TRD. All three factors improved over 4 weeks of treatment with esketamine nasal spray.

Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study.

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study.

BACKGROUND: Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). METHODS: To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. RESULTS: Mixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥ 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: -4.9 (-8.98; -0.80) and -0.7 (-5.16; 3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea. CONCLUSIONS: A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥ 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified. REGISTRATION: ClinicalTrials.gov Identifier: NCT03227224. PREVIOUS PRESENTATION: Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.

Genome-wide association study and polygenic risk score analysis of esketamine treatment response.

To elucidate the genetic underpinnings of the antidepressant efficacy of S-ketamine (esketamine) nasal spray in major depressive disorder (MDD), we performed a genome-wide association study (GWAS) in cohorts of European ancestry (n = 527). This analysis was followed by a polygenic risk score approach to test for associations between genetic loading for psychiatric conditions, symptom profiles and esketamine efficacy. We identified a genome-wide significant locus in IRAK3 (p = 3.57 × 10-8, rs11465988, ß = - 51.6, SE = 9.2) and a genome-wide significant gene-level association in NME7 (p = 1.73 × 10-6) for esketamine efficacy (i.e. percentage change in symptom severity score compared to baseline). Additionally, the strongest association with esketamine efficacy identified in the polygenic score analysis was from the genetic loading for depressive symptoms (p = 0.001, standardized coefficient ß = - 3.1, SE = 0.9), which did not reach study-wide significance. Pathways relevant to neuronal and synaptic function, immune signaling, and glucocorticoid receptor/stress response showed enrichment among the suggestive GWAS signals.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

BACKGROUND: Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. METHODS: This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression-Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. RESULTS: Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. CONCLUSIONS: These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program.

BACKGROUND: An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). Transient cardiovascular stimulatory effects have been reported with ketamine. METHODS: Cardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine-treated adults with TRD in six trials (five double-blind, placebo-controlled (486 placebo-treated patients); one open-label) of 4-52 weeks' duration. Patients with established cardiovascular disease, including uncontrolled hypertension (> 140/> 90 mmHg), history of hypertensive crisis, or clinically significant electrocardiogram (ECG) abnormalities, were excluded from enrollment. Effects on cardiac repolarization were assessed in a phase I randomized, positive- and active-controlled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated. RESULTS: Adverse events related to increased BP were reported in 12.8% of all esketamine-treated patients (in double-blind trials: esketamine/antidepressant 11.6% vs. antidepressant/placebo 3.9%; OR 3.2 [1.9-5.8]). Among the patients without a history of hypertension, new antihypertensive medication was initiated by 2.1% (6/280) of patients in the esketamine/antidepressant group versus 1.2% (2/171) of patients in the antidepressant/placebo group, in the double-blinded studies. Adverse events related to abnormal heart rate were reported in 3.0% of all esketamine-treated patients (in double-blind trials: 1.6% vs. 0.8%; OR 1.9 [0.5-8.6]). Overall, three cardiovascular adverse events related to BP increase were reported as serious and severe, and there was one fatal event considered unrelated (acute cardiac failure). BP increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h postdose. In two studies (4-week duration, age 18-64 years), the largest mean maximum systolic/diastolic postdose BP increases were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo, and in a short-term elderly study (age ≥ 65 years) were 16.0/9.5 and 11.1/6.8 mmHg, respectively. Across studies/study phases, < 2% of patients discontinued esketamine due to adverse events of increased BP and tachycardia. No clinically relevant effect on ECG parameters was observed. Therapeutic and supratherapeutic doses of esketamine did not prolong the QTcF (QT corrected by Fridericia's equation) interval (baseline-corrected values of - 2.02 to 2.16 ms, and - 3.51 to 4.89 ms, respectively). CONCLUSIONS: BP elevations following esketamine dosing are generally transient, asymptomatic, and not associated with serious cardiovascular safety sequalae. Further evaluation of long-term cardiovascular outcomes is warranted.

Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. METHODS: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. RESULTS: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. CONCLUSIONS: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094378.

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study.

RATIONALE: The purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance. METHODS: Twenty-six healthy volunteers aged 21 to 60 years were enrolled in this study. In the evening, 8 h after treatment administration, participants conducted the standardized 100-km on-road driving test. Primary outcome measure was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Mean lateral position, mean speed, and standard deviation of speed were secondary outcome measures. For SDLP, non-inferiority analyses were conducted, using +2.4 cm (relative to placebo) as a predefined non-inferiority margin for clinical relevant impairment. RESULTS: Twenty-four participants completed the study. No significant SDLP difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001). The upper limit of the two-sided 95% confidence interval (CI) of the mean difference between esketamine and placebo was +0.86 cm, i.e., <+2.4 cm, thus demonstrating that esketamine was non-inferior to placebo. Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo). No significant differences in mean speed, standard deviation of speed, and mean lateral position were observed between the active treatments and placebo. CONCLUSIONS: No significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo. In contrast, oral mirtazapine (30 mg) significantly impaired on road driving performance.

Single-dose Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Selective Inhibitor of Sodium Glucose Cotransporter 2, in Healthy Indian Participants.

PURPOSE: Canagliflozin, an orally active selective inhibitor of sodium glucose cotransporter 2, has been approved in several countries for the treatment of type 2 diabetes mellitus. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose canagliflozin 200 or 300 mg in healthy Indian participants. METHODS: In this Phase 1, single-center, open-label, 2-period crossover study, healthy adult participants were randomly assigned to receive a single dose of canagliflozin 200 mg in period 1, followed by canagliflozin 300 mg in period 2, or vice versa. The 2 periods were separated by a washout interval of 14 days. The PK and PD properties and tolerability of canagliflozin were assessed at prespecified time points. FINDINGS: Of 15 randomized participants, 14 completed the study. After the administration of single doses of 200 and 300 mg, the mean (SD) Cmax values were 1792 (430) ng/mL and 2789 (941) ng/mL, respectively; AUC0-∞, values were 18,706 (3818) ng·h/mL and 28,207 (5901) ng·h/mL, respectively. The Tmax and t½ of canagliflozin were independent of dose (Tmax, 1.5 hours at both doses; t½, 13.0 and 12.6 hours with 200 and 300 mg). Over the first 4 hours, mean (SD) renal threshold for glucose (RTG) values were 60.8 (8.90) and 61.2 (7.04) mg/dL with the 200- and 300-mg doses, respectively. No effect on plasma glucose concentrations over 0 to 4 hours relative to baseline was observed with either dose. The only treatment-emergent adverse event (TEAE) reported in >1 participant was dizziness (2 participants with the 200-mg dose). None of the participants in the 300-mg group reported any TEAEs. No deaths, discontinuations due to TEAEs, or hypoglycemic episodes were reported. IMPLICATIONS: The mean plasma exposure (Cmax and AUC) to canagliflozin increased in a dose-dependent manner after the administration of single-dose oral canagliflozin 200 and 300 mg in these healthy Indian participants. The Tmax and t½ of canagliflozin appeared to be independent of dose. Overall, PK characteristics were consistent with previous findings in other ethnic populations. The reductions in RTG with canagliflozin were similar to those reported in Western participants, whereas the amount of urinary glucose excretion was somewhat less than those previously observed in studies in Western participants. Canagliflozin was generally well tolerated in these healthy Indian participants. ClinicalTrials.gov identifier: NCT01748526.

Pharmacokinetics and pharmacodynamics of once- and twice-daily multiple-doses of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants.

AIMS: Assess the steady-state pharmacokinetics, pharmacodynamics and safety of once-daily (q.d.) versus twice-daily (b.i.d.) dosing with canagliflozin at the same total daily doses of 100 and 300 mg in healthy participants. METHODS: 34 participants (17 in each cohort) were enrolled in this single-center, open-label, multiple-dose, 2-cohort, 2-way crossover study. Participants in each cohort received a total daily dose of either 100 or 300 mg canagliflozin for 5 days with q.d. then b.i.d. dosing or vice versa. Pharmacokinetics and pharmacodynamics were assessed on day 5 of each period. RESULTS: The canagliflozin Cmax,ss of 100 and 300 mg q.d. dosing were higher by 66% and 72% than corresponding morning Cmax,ss of the 50 mg and 150 mg b.i.d. regimen, respectively. The geometric mean ratios (90% CI) of b.i.d./q.d. for AUC0-24h,ss at total doses of 100 and 300 mg were 97.08 (94.08; 99.62) and 99.32 (94.71; 104.16) respectively. Median tmax and mean t1/2 were independent of dose and regimen. Mean (SE) 24-h mean renal glucose threshold values for b.i.d. and q.d. regimens were 59.2 (1.03) and 60.2 (1.03) mg/dL for the 100 mg daily doses and 51.0 (1.04) and 52.5 (1.04) mg/dL for the 300 mg daily doses. Mean (SE) values of 24-h urinary glucose excretion for b.i.d. and q.d. regimens were 52.8 (1.94) and 48.6 (1.94) g for the 100 mg daily doses and 58.6 (3.81) and 57.8 (3.81) g for the 300 mg daily doses. Both doses were safe and well tolerated. CONCLUSION: Pharmacokinetics and pharmacodynamics of canagliflozin administered q.d. relative to b.i.d. at the same 100 and 300 mg total daily doses were comparable. Overall, canagliflozin was well tolerated.

Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor.

PURPOSE: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. METHODS: Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7-9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin's pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. FINDINGS: Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-∞ values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0-∞ values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal function, however. The amount of UGE declined as renal function decreased, whereas RTG was not suppressed to the same extent in the moderate to severe renal impairment groups (mean RTG, 93-97 mg/dL) compared with the mild impairment and normal function groups (mean RTG, 68-77 mg/dL). IMPLICATIONS: Canagliflozin's pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576.

Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants.

Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants.

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. METHODS: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). RESULTS: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. CONCLUSION: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants.

OBJECTIVE: To evaluate the pharmacokinetics of oral canagliflozin and its O-glucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated. METHODS: In this open-label, single- (day 1) and multiple-dose (days 4-9), parallel-group, phase 1 study, 27 healthy participants were randomized into three groups (1:1:1) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre-pecified timepoints on days 1, 9, and 10. RESULTS: Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination half-lives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI): 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI: 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed. CONCLUSION: Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants.

Effect of food on the pharmacokinetics of canagliflozin/metformin (150/1,000 mg) immediate-release fixed-dose combination tablet in healthy participants.

OBJECTIVE: To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. METHODS: A randomized, open-label, singlecenter, single-dose, 2-period, 2-sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10-14 day washout between treatments PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. RESULTS: When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUC∞, and Cmax were within the bioequivalence limits of 80-125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. CONCLUSIONS: Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin.

Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

BACKGROUND: Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated. OBJECTIVE: This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants. METHODS: This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated. RESULTS: Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUCτ,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08-1.17) and 1.15 (1.06-1.25), respectively. AUCτ,ss and Cmax,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was -0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments. CONCLUSIONS: Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.

Reproducibility of 3.0 Tesla magnetic resonance spectroscopy for measuring hepatic fat content.

PURPOSE: To investigate reproducibility of proton magnetic resonance spectroscopy ((1)H-MRS) to measure hepatic triglyceride content (HTGC). MATERIALS AND METHODS: In 24 subjects, HTGC was evaluated using (1)H-MRS at 3.0 Tesla. We studied "between-weeks" reproducibility and reproducibility of (1)H-MRS in subjects with fatty liver. We also studied within liver variability and within day reproducibility. Reproducibility was assessed by coefficient of variation (CV), repeatability coefficient (RC), and intraclass correlation coefficient (ICC). RESULTS: The CV of between weeks reproducibility was 9.5%, with a RC of 1.3% HTGC (ICC 0.998). The CV in fatty livers was 4.1%, with a RC of 1.3% HTGC (ICC 0.997). Within day CV was 4.5%, with a RC of 0.4% HTGC (ICC 0.999). CV for within liver variability was 14.5%. CONCLUSION: Reproducibility of (1)H-MRS to measure HTGC for "between-weeks" measurements and in fatty livers is high, which is important for follow-up studies. Within liver variability displays a larger variation, meaning that liver fat is not equally distributed and during consecutive measurements the same voxel position should be used.