Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism.

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.

Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects.

PURPOSE: To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects. METHODS: This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45 years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1-6) followed by 2 mg once daily on days 7-12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC). RESULTS: Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6 ng/mL) was achieved in 4 h (median Tmax,ss; range, 1.58-8.00) and the geometric mean AUCtau,ss was 546 h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median Tmax remained unchanged (4 h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L. CONCLUSIONS: The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study
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OBJECTIVE: To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected inactive metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). METHODS: The study enrolled subjects with severe RI (n = 8) and matched HS (n = 8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥ 50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects vs. HS. All subjects received a single oral dose of siponimod 0.25 mg on day 1; PK and safety were evaluated during the follow-up (~ 13 days). RESULTS: PK of siponimod was marginally affected in severe RI subjects vs. HS: Cmax decreased by 8%, and AUClast and AUCinf increased by 23% and 24%, respectively; half-life (37 vs. 26 hours) and systemic clearance (2.9 vs. 3.4 L/h) were comparable. Siponimod plasma unbound (u) fraction at 4 hours post-dose was similar between the two groups (range: 0.0172 - 0.0550%). Cmax(u) was comparable while AUClast(u) and AUCinf(u) were increased by 33% compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment (RI) compared with matched HS. No adverse events were reported during this study. CONCLUSIONS: Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further to severe RI, investigation of PK in subjects with mild and moderate RI was not warranted.
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Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study
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OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. RESULTS: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. CONCLUSIONS: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI.
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Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects.

OBJECTIVE: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects. METHODS: Healthy subjects (n=76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed. RESULTS: Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses>3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment. CONCLUSIONS: Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol.

Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women.

OBJECTIVE: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). METHODS: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18-40 years. In period 1, a single oral dose of an OC containing 30 µg ethinyl estradiol (EE)/150 µg levonorgestrel (LNG) was administered alone. In period 2, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods. RESULTS: The geometric mean ratios of EE Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval (CI): 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63-0.73), respectively. CONCLUSIONS: In conclusion, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.

Effect of oral siponimod (BAF312) on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive in healthy female subjects.

OBJECTIVE: To evaluate the effects of siponimod (BAF312) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a monophasic oral contraceptive (OC). MATERIALS AND METHODS: This was a phase 1, single-center, open-label, multipledose, single-sequence study in healthy females. Eligible subjects (n = 23) were exposed sequentially to two treatment periods: period 1 (OC alone) and period 2 (OC + siponimod) in two consecutive menstrual periods. PK parameters were assessed on day 21 of both treatment periods. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone concentrations were measured at baseline and days 3, 6, 8, 11, 14, 16, 19, 21, and 23 of each period. Largest ovarian follicle size and sex hormone-binding globulin (SHBG) concentration were measured and Hoogland score was calculated at baseline and day 21 of each period. Safety and tolerability of siponimod was also assessed. RESULTS: Co-administration (OC + siponimod) increased the AUC(τ,ss) and C(max,ss) of levonorgestrel by 28% and 18%, respectively, but had no effect on the PK of ethinylestradiol. No significant changes in estradiol, FSH, and LH were noted with co-administration vs. OC alone. Progesterone levels < 5 nmol/L, largest follicle size < 10 mm, and Hoogland score of 1 on day 21 indicated lack of ovulation in all subjects during co-administration. Co-administration was well tolerated. CONCLUSION: In conclusion, PK and PD of the OC were not altered to a clinically significant extent and contraceptive efficacy was maintained with co-administration. Hence, OC as a contraceptive measure can be safely co-administered with siponimod.

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.

AIM: Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. METHODS: Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. RESULTS: Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⁻¹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. CONCLUSION: Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized, Open-label Study in Healthy Subjects.

PURPOSE: The goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects. METHODS: This randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h). FINDINGS: No clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans. IMPLICATIONS: Siponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.

A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.

Umibecestat, an orally active ß-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA).

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

OBJECTIVES: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). METHODS: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. CONCLUSIONS: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.

Impact of siponimod on vaccination response in a randomized, placebo-controlled study.

OBJECTIVE: To evaluate effects of siponimod on response to T-cell-dependent (influenza) and T-cell-independent (pneumococcal polysaccharide vaccine [PPV-23]) vaccinations in healthy participants. METHODS: In this double-blind, placebo-controlled, parallel-group study, each participant underwent a 7-week treatment period and received intramuscular injections of influenza and PPV-23 vaccines (day 21). Participants were randomized to 4 treatment groups (N = 30 each) and received placebo or siponimod 2 mg once daily in concomitant, interrupted, or preceding fashion. Individual response to vaccination was defined by a ≥4-fold (influenza) antibody titer increase and by a ≥2-fold increase in serotype-specific immunoglobulin (Ig) G concentrations (PPV-23) on day 28 vs baseline. Responder rates were compared using noninferiority analysis. RESULTS: Mean influenza titers were similar to placebo in the preceding and interrupted groups but lower in the concomitant group. The proportion of participants with influenza titers ≥40 four weeks after vaccination (seroprotection) was similar to placebo across all groups and antigens. In each treatment group, response criteria were met for 3 of 4 antigens including H1N1 and H3N2. A noninferior response was determined in the context of preceding treatment but not interrupted or concomitant treatment. Regarding PPV-23, approximately 90%-100% of participants exhibited a ≥2-fold increase in IgG concentrations vs baseline. Noninferior responder rates were determined for each siponimod treatment group. CONCLUSIONS: Siponimod treatment had no relevant effect on antibody response to PPV-23. European Medicines Agency response criteria were essentially met for influenza, but titers were lower on concomitant treatment. Overall, these data suggest that siponimod has limited effect on the efficacy of vaccinations with neoantigens. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in healthy persons, siponimod had limited effect on the immune response following influenza or pneumococcal vaccinations.

Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo.

Modified-release (MR) zolpidem was developed to maintain effective plasma concentrations during the 3- to 6-hour post-dosage interval, corresponding to the middle portion of the typical sleep interval. Modified-release zolpidem (12.5 mg), standard immediate-release (IR) zolpidem (10 mg), and placebo were compared in a double-blind, single-dose, 3-way crossover daytime study of healthy volunteers (n = 70 completers). Effect areas for electroencephalographic beta amplitude during 0 to 8 hours and 3 to 6 hours after dosage were greater for MR compared to IR (P < .001). The digit-symbol substitution test and sedation rating scales behaved similarly. MR and IR did not differ in effects at 8 hours post-dosage nor in halflife or clearance. Time of peak plasma concentration (tmax) was significantly longer for MR (2.4 vs 2.0 hours, P < .004), and dose-normalized peak plasma concentration (Cmax) was lower (12.2 vs 14.0 ng/mL/mg, P < .001). MR zolpidem also had greater area under the plasma concentration curve (AUC) during the 3- to 6-hour interval (P < .001). Thus, MR zolpidem produces sustained plasma levels compared to IR, with resulting enhancement of pharmacodynamic effects in the 3- to 6-hour post-dosage interval.

Cardiac Effects of Siponimod (BAF312) Re-initiation After Variable Periods of Drug Discontinuation in Healthy Subjects.

PURPOSE: The goal of this study was to investigate the effect of siponimod treatment re-initiation on the initial negative chronotropic effects and cardiac rhythm after variable drug discontinuation periods. METHODS: This partially double-blind, randomized, placebo-controlled study was conducted in healthy subjects. Siponimod doses (0.5-4.0 mg) and placebo were evaluated in combination with drug discontinuation periods ranging from 48 to 192 hours. Twelve-lead Holter ECGs were performed from 1.5 hours before until 24 hours after single-dose re-initiation. Atrioventricular blocks (AVBs) and sinus pauses (RR >2 seconds) were categorized according to dose level, discontinuation period, and resting and nonresting hours. FINDINGS: Of the enrolled 138 subjects, 117 were evaluated. Demographic and baseline characteristics were comparable between the treatment groups. Subjects rechallenged at the combination of 4 mg/192 hours (highest investigated dose and longest discontinuation period [7 missed doses]) exhibited the highest decrease in pooled, placebo-adjusted heart rate (HR) of 14.53 beats/min. The magnitude of the negative chronotropic effect of siponimod re-initiation was dependent on both dose and duration of treatment discontinuation. Regardless of the dose, the placebo-adjusted HR reduction at re-initiation of drug treatment after up to 96 hours of drug discontinuation remained <10 beats/min. Except for 1 outlier for HR decrease under the 96-hour/placebo combination, no outliers were observed for any combination up to and including the 96-hour discontinuation periods. Most of the AVBs and sinus pauses were observed during nocturnal hours concurrent with increased vagal tone. All detected AVBs and sinus pauses were asymptomatic and not considered clinically relevant. IMPLICATIONS: Siponimod could be safely re-initiated without retitration after drug discontinuation periods up to 96 hours. Retitration is required if patients miss ≥ 4 consecutive doses.

Intravenous Dosing as an Alternate Approach to Safely Achieve Supratherapeutic Exposure for Assessments of Cardiac Repolarization: A Randomized Clinical Trial with Mavoglurant (AFQ056).

PURPOSE: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS: This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS: This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.

Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects.

PURPOSE: The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. METHODS: The study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days -1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated. FINDINGS: Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure. IMPLICATIONS: The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.

Distinct effects of IPSU and suvorexant on mouse sleep architecture.

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305), and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R preferring antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (IPSU) has allowed us to test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU inducing sleep primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, our goal was to determine whether suvorexant and IPSU affect sleep architecture independently of overall sleep induction. We therefore tested suvorexant (25 mg/kg) and IPSU (50 mg/kg) in mice during the inactive phase (lights on) when sleep is naturally more prevalent and when orexin levels are normally low. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 h after dosing. At the doses tested, suvorexant significantly decreased wake only during the first hour and IPSU did not affect wake time. These data suggest that OX2R preferring antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of OX2R antagonists vs. DORAs remains to be seen.

A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers.

AIM: To assess residual psychomotor and cognitive effects of a modified-release formulation of zolpidem (zolpidem-MR), developed to provide sustained hypnotic efficacy during the whole night, compared with placebo and flurazepam. METHODS: Twenty-four healthy elderly volunteers received four study treatments (zolpidem-MR 6.25 mg and 12.5 mg, placebo and flurazepam 30 mg) using a randomized, cross-over, double-blind design. Residual psychomotor and cognitive effects were assessed with a psychometric test battery. Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire. RESULTS: Psychometric performance was significantly impaired with flurazepam but not with zolpidem-MR at either dose. Ease of falling asleep and sleep quality were significantly improved with both doses of zolpidem-MR and with flurazepam. Neither active drug modified perception of well-being on awakening. CONCLUSION: In elderly subjects, zolpidem-MR showed no residual functional impairment in psychometric or cognitive tests sensitive to flurazepam.

A double-blind, placebo- and flurazepam-controlled investigation of the residual psychomotor and cognitive effects of modified release zolpidem in young healthy volunteers.

Short-acting hypnotic drugs, such as zolpidem, have minimal residual effects but may not provide optimal efficacy throughout the night for all insomnia patients. A modified-release formulation of zolpidem, zolpidem-MR, has been developed to overcome this limitation. This was a phase I, double-blind, 3-way crossover, placebo-controlled study to investigate the residual psychomotor and cognitive effects of a single oral dose of zolpidem-MR 12.5 mg in 18 healthy young adults. Flurazepam 30 mg was used as a positive control. No comparison with standard immediate-release zolpidem was made. Five neuropsychological tests and 2 subjective tests were performed 8 hours after dosing. The safety of zolpidem-MR was also investigated. Performance on the Critical Flicker Fusion Frequency test, Choice Reaction Time, Immediate and Delayed Word Recall, and the Compensatory Tracking Task was significantly impaired by flurazepam but not by zolpidem-MR (with the exception of the Compensatory Tracking Task) or placebo. No significant effects were observed on the Digit Symbol Substitution Test. The Leeds Sleep Evaluation Questionnaire showed that both drugs improved the ease of getting to sleep and perceived quality of sleep, whereas only flurazepam significantly impaired the ease of awakening. Neither drug scored significantly better than placebo on the Bond and Lader contentedness scale, but both induced a significant difference in calmness; only flurazepam significantly reduced alertness. The safety profile of zolpidem-MR was comparable to placebo. In conclusion, the study showed the good tolerance of zolpidem-MR in terms of residual neuropsychological effects as well as a beneficial effect on sleep quality in young healthy adults.

Lack of effect of amisulpride on the pharmacokinetics and safety of lithium.

Lithium may be used as adjuvant therapy in schizophrenic patients and antipsychotics can be employed during the early phases of lithium therapy in patients with bipolar disorder. The issue of interactions between lithium and antipsychotics is therefore important. This study investigates the potential influence of repeated administration of amisulpride, an atypical antipsychotic, on the pharmacokinetics of lithium at steady state. Twenty-four healthy male volunteers (aged 1833 yr) received lithium carbonate (500 mg b.i.d.) for 14 d. All subjects were shown to have stable lithium serum concentrations after 57 d and were then randomized to receive double-blind administration of amisulpride (100 mg b.i.d.) or placebo bid from day 8 of lithium administration. Complete pharmacokinetic profiles were obtained on days 7 and 14 for lithium and trough plasma concentrations on days 10, 12 and 14 for amisulpride. Co-administration of amisulpride appeared to exert no effect on the pharmacokinetics of lithium. All treatments were well tolerated and safety assessment revealed no differences between the lithium+placebo and lithium+amisulpride groups. This finding permits the flexible use of amisulpride in patients already receiving lithium therapy.