Dataset Information

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT_1A Receptor Agonist for the Treatment of Schizophrenia.

ABSTRACT:

Purpose

Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT_1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103.

Methods

Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront.

Results

Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species.

Conclusions

Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.

SUBMITTER: Xiao G

PROVIDER: S-EPMC9160101 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT<sub>1A</sub> Receptor Agonist for the Treatment of Schizophrenia.

Xiao Guangqing G Chen Yu-Luan YL Dedic Nina N Xie Linghong L Koblan Kenneth S KS Galluppi Gerald R GR

Pharmaceutical research 20220428 5

<h4>Purpose</h4>Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT<sub>1A</sub> agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103.<h4>Methods</h4>Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were con ...[more]

PMID: 35484370

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Project description:Background and objectivesUlotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP).MethodsPatients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point).ResultsThe efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%).DiscussionIn this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment.Trial registration informationClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016.Classification of evidenceThis Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.

Project description:Background and objectivesIn clinical trials, the safety of drugs is summarized by the incidence of adverse events, while post-marketing reporting systems use disproportionate reporting of adverse drug reactions. Here, we propose a method to evaluate the novelty of a safety profile of a drug in a new class (in clinical trials), against that of those already on the market (using pharmacovigilance data).MethodsThrough Bayesian disproportionality analyses of the US Food and Drug Administration Adverse Event Reporting System (FAERS) data, we identified and ranked Preferred Terms for a pool of 30 antipsychotics. Adverse event rates in randomized, double-blind, placebo-controlled schizophrenia clinical trials were summarized by their class specificity. One study (N = 245) of the trace amine-associated receptor 1 (TAAR1) agonist ulotaront (SEP-363856) was compared with five studies of dopamine D2 receptor-based antipsychotics lurasidone (N = 1041), quetiapine (N = 119), olanzapine (N = 122), and placebo (N = 504).ResultsIn clinical trials of antipsychotics, cumulative rates for adverse events at and above a threshold of disproportional reporting (Empirical Bayes Geometric Mean 50 > 3 in FAERS) were 52%, 42%, and 60% for lurasidone, quetiapine, and olanzapine, respectively, indicating that over half of the adverse events reported in clinical trials of an atypical antipsychotic are class-specific risks. In contrast, in the clinical trial of ulotaront, the cumulative rate was 23%, indicating a lower rate of antipsychotic class-specific risk.ConclusionsThese results demonstrate a novel approach to summarize adverse events in clinical trials, where the cumulative burden of class-specific risks describes the emerging safety profile of a new drug in clinical development, relative to reactions anticipated for drugs in an established pharmacological class. CLINICALTRIALS.Gov identifiersNCT0296938, NCT00088634, NCT00549718, NCT00615433, NCT00790192.

Dataset Information

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT_1A Receptor Agonist for the Treatment of Schizophrenia.

Purpose

Methods

Results

Conclusions

Publications

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT<sub>1A</sub> Receptor Agonist for the Treatment of Schizophrenia.

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Dataset Information

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia.

Purpose

Methods

Results

Conclusions

Publications

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT<sub>1A</sub> Receptor Agonist for the Treatment of Schizophrenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT_1A Receptor Agonist for the Treatment of Schizophrenia.