Lithium + Valproic Acid + KarXT for Healthy Subjects

Recruiting at 1 trial location

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Karuna Therapeutics

Disqualifiers: Cardiovascular, Hepatic, Renal, Pancreatitis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the effects of lithium and valproic acid on the single-dose pharmacokinetics (PK) of KarXT and the effect of KarXT on the single-dose PK of lithium and valproic acid in healthy participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the study involves healthy participants, it is likely that you should not be on any regular medications. Please consult with the study team for specific guidance.

What evidence supports the effectiveness of the drug Lithium in treating various conditions?

Research shows that lithium carbonate is effective in treating mania and bipolar disorders, and it may also help with unipolar depression, aggressive behavior, and certain movement disorders. It has potential uses in other conditions like asthma and thyroid diseases, suggesting its broad therapeutic potential. ^{1 2 3 4 5}

What makes the drug Lithium + Valproic Acid + KarXT unique compared to other treatments?

This drug combination is unique because it combines lithium, known for its mood-stabilizing effects, with valproic acid, which has anticonvulsant properties, and KarXT, a novel compound that may offer additional benefits. The combination aims to enhance therapeutic effects while potentially reducing side effects compared to using each component alone. ^{2 4 6 7 8}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for healthy individuals who can safely take the medications lithium, valproic acid, and KarXT. Specific eligibility criteria are not provided, but typically participants must meet certain health standards to ensure their safety during the study.

Inclusion Criteria

I am healthy, not able to have children, and all my medical tests are normal.

My BMI is between 18.0 and 32.0.

Exclusion Criteria

I have had pancreatitis before.

I have a history of urinary, gastric issues, glaucoma, prostate enlargement, or frequent nighttime urination.

Other protocol-defined Inclusion/Exclusion criteria apply

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part A

Evaluation of the effects of lithium and valproic acid on the single-dose pharmacokinetics of KarXT

1 week

Part B

Evaluation of the effects of KarXT on the single-dose pharmacokinetics of lithium and valproic acid

1 week

Part C

Continuation of pharmacokinetic evaluations with different dosing sequences

1 week

Part D

Final evaluation phase of pharmacokinetic interactions

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Lithium (Other)
• Valproic Acid (Other)
• Xanomeline/Trospium Chloride (Other)

Trial Overview The study is testing how taking lithium or valproic acid might affect the levels of a drug called KarXT in the body, and also how KarXT affects the levels of lithium and valproic acid when taken by healthy people.

Participant Groups

Group I: Part D Experimental Treatment 2 Interventions

Group II: Part C Experimental Treatment 2 Interventions

Group III: Part B Experimental Treatment 2 Interventions

Group IV: Part A Experimental Treatment 2 Interventions

Lithium is already approved in Canada, Japan for the following indications:

Approved in Canada as Lithium for:

• Bipolar disorder
• Manic episodes
• Major depressive disorder

Approved in Japan as Lithium for:

• Bipolar disorder
• Manic episodes

Who Is Running the Clinical Trial?

Karuna Therapeutics

Lead Sponsor

Trials

17

Recruited

4,100+

Findings from Research

In a double-blind study of severely ill hospitalized manic patients, lithium carbonate and haloperidol significantly improved manic symptoms without causing sedation, while chlorpromazine caused sedation but did not effectively address mania.

Lithium carbonate provided a more consistent and comprehensive improvement in manic symptoms, leading to a higher discharge rate of patients compared to those treated with haloperidol or chlorpromazine, highlighting its potential as a more effective treatment for mania.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Shopsin, B., Gershon, S., Thompson, H., et al.[2019]

In a study involving 12 healthy volunteers, the bioavailability of two extended-release lithium carbonate products (Eskalith CR and Lithobid) was found to be significantly different from an immediate-release product (Lithotab), with Eskalith CR showing a 40% lower peak plasma concentration compared to Lithotab.

The immediate-release product, Lithotab, reached its maximum plasma concentration faster than the extended-release products, indicating that the formulation affects how quickly lithium enters the bloodstream, although the total amount excreted in urine was similar across all products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose bioavailability of two extended-release lithium carbonate products. Kirkwood, CK., Wilson, SK., Hayes, PE., et al.[2013]

A new sustained-release lithium carbonate (LC) tablet formulation containing 15% carbopol was developed, which allows for smoother and extended absorption, similar to the commercial Eskalith CR, while preventing high peak blood levels that can cause side effects.

This formulation can be administered twice daily instead of three to four times, improving patient compliance during maintenance therapy for conditions like bipolar disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Formulation of sustained - release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. Emami, J., Tavakoli, N., Movahedian, A.[2013]

In a study involving 5 normal volunteers, both lithium carbonate ('Priadel') and lithium citrate ('Litarex') showed similar total bioavailability when administered at the same dose (27.2 mmol lithium).

However, lithium citrate resulted in a significantly lower peak serum lithium level compared to lithium carbonate, indicating differences in how the body processes these two formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of lithium carbonate and lithium citrate: a comparison of two controlled-release preparations. Tyrer, SP., Peat, MA., Minty, PS., et al.[2013]

Lithium carbonate (Li2CO3) is well-established for treating and preventing mania and bipolar disorders, but recent studies suggest it may also be effective for unipolar depression, aggression, schizophrenia, and other non-psychiatric conditions.

The review highlights potential new uses for lithium in treating various conditions such as movement disorders, asthma, and sleep disorders, indicating a need for further double-blind studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical uses of lithium salts. Frost, RE., Messiha, FS.[2019]

Lithium valproate exhibits significant anticonvulsant activity similar to sodium valproate, effectively reducing seizures in experimental models.

The addition of lithium ions alters the neurochemical profile of valproate, increasing levels of GABA and glutamate in the brain, which may contribute to its sedative and tranquilizing effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lithium valproate: its neuropharmacological spectrum and effect on transmitter amino acid content of the brain of rats]. Kharlamov, AN., Shumkova, OV., Blinkova, NF., et al.[2013]

The novel lithium complex medication showed a different pattern of brain electrical activity compared to lithium carbonate, indicating it may induce milder activation of the cerebral cortex.

This new formulation, which includes lithium citrate, aluminum oxide, and polymethylsiloxane, is suggested to be more effective and safer than traditional lithium carbonate for treating neurological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Lithium Preparations on Cerebral Electrophysiological Activity in Rats. Konenkov, VI., Rachkovskaya, LN., Letyagin, AY., et al.[2018]

In a study involving eight healthy volunteers, lithium carbonate showed a mean biological half-life of approximately 16.5 hours, indicating a slow disposition rate which is important for its therapeutic use.

The controlled release formulation of lithium carbonate resulted in a smoother serum concentration profile, with a 22% lower peak concentration and a delayed time to peak, suggesting it may provide a more stable delivery of the drug compared to the immediate release tablet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption and disposition kinetics of lithium carbonate following administration of conventional and controlled release formulations. Arancibia, A., Corvalan, F., Mella, F., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Single-dose bioavailability of two extended-release lithium carbonate products. [2013]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Formulation of sustained - release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Bioavailability of lithium carbonate and lithium citrate: a comparison of two controlled-release preparations. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical uses of lithium salts. [2019]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Lithium valproate: its neuropharmacological spectrum and effect on transmitter amino acid content of the brain of rats]. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Effect of Lithium Preparations on Cerebral Electrophysiological Activity in Rats. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Absorption and disposition kinetics of lithium carbonate following administration of conventional and controlled release formulations. [2013]