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 β-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.

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.

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.

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.

Metabolism and Disposition of Siponimod, a Novel Selective S1P/S1P 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 [C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured.

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.

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study .

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.

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 C values while controlling tolerability.

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study .

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.

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.

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.

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).

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.

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.

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.

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.

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).

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.

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.

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.