Method for optimizing 5-hydroxytryptamine function in the brain for therapeutic purposes

Inventors

Jacobsen, Jacob Pade Ramsoe

Assignees

Evecxia Therapeutics Inc

Abstract

Disclosed herein are methods of elevating brain extracellular 5-hydroxytryptamine (5-HTExt) and of treating psychiatric conditions and neurological disorders using continuous intravenous infusion of 5-hydroxytryptophan (5-HTP). The methods can be provided for treatment of acute suicidal ideation and/or acute worsening of a mood disorder. The methods can provide rapid onset of therapeutic effect while also having low incidence of acute or moderate adverse effects. Also described herein are compositions for use in the methods, including stable 5-HTP compositions for use in preparing infusate solutions.

Core Innovation

The disclosed invention relates to rapid elevation of brain extracellular 5-hydroxytryptamine (5-HTExt) in a human subject by administering 5-hydroxytryptophan (5-HTP) as a continuous intravenous (IV) infusion. The method uses an average 5-HTP infusion rate of about 0.01 milligrams per kilogram bodyweight per hour (mg/kg/hr) to about 0.125 mg/kg/hr for an infusion treatment period of about 4 hours or more, and is free of administering a peripheral decarboxylase inhibitor (PDI) to the subject.

A key feature is defining the 5-HTP plasma exposure using an AUCInf (area under the curve of a plasma concentration versus time curve extrapolated to infinity) expressed in hours times nanograms per milliliter (h×ng/ml). The exposure is stated to be predictable to be about the value calculated by AUCInf = 3500×IV dose of 5-HTP, where the IV dose is the total dose of 5-HTP administered over the infusion treatment period expressed in mg/kg.

The disclosure further addresses infusion profile designs including constant versus variable/ramp infusion profiles and relates these to predictable exposure. It also describes optional co-therapy with 5-HTExt-elevating agents, including serotonin reuptake inhibitors such as escitalopram and serotonin 5-HT3 receptor antagonists as anti-emetics, and additional embodiments include post-infusion slow-release 5-HTP within about 24 hours.

The problem addressed is the need for rapid and controlled elevation of brain extracellular 5-hydroxytryptamine (5-HTExt) with predictable 5-HTP exposure. The disclosure states that the continuous infusion approach provides controlled and predictable plasma levels, rapid onset, and reduced gastrointestinal/serotonin toxicity, and reports tolerability and pharmacodynamics including dose proportionality and cortisol changes as evidence of target engagement.

Claims Coverage

The document provides two independent claims. Independent claims define continuous IV infusion of 5-HTP with specified infusion-rate and treatment-period constraints while excluding peripheral decarboxylase inhibitor (PDI) administration, and define predictable 5-HTP plasma exposure using an AUCInf relationship. There are four inventive features repeated across the independent claims.

Across the independent claims, the inventive core is continuous IV infusion of 5-HTP at an average infusion rate of about 0.01–0.125 mg/kg/hr for about 4 hours or more to achieve predictable 5-HTP plasma exposure defined by AUCInf = 3500×(total IV dose), while the method is free of administering a peripheral decarboxylase inhibitor (PDI). The first independent claim further frames this exposure as elevating brain extracellular 5-HTExt in a human subject.

Stated Advantages

Documented Applications