Drug Database: Pyridostigmine

Pharmacology

Pharmacology

Mechanism of Action

Immune modulator.² Pyridostigmine is a reversible acetylcholinesterase inhibitor that is FDA-approved for treating myasthenia gravis and reversing the effects of muscle relaxants.^4–6 It has also been approved for use by military personnel as a pretreatment for exposure to the chemical nerve agent Soman.⁷ Pyridostigmine works by inhibiting the acetylcholinesterase (AChE) enzyme from breaking down the neurotransmitter acetylcholine (ACh), and thereby increases the bioavailability of ACh and enhances the transmission of nerve impulses at neuromuscular junctions.^3–5

As a potential HIV immune modulator, pyridostigmine is thought to simulate the effect of the cholinergic anti-inflammatory pathway (CAP). The CAP is a physiological neural reflex that regulates the immune system and suppresses inflammation through the release of ACh and subsequent modification of cytokine production.^4,8 In a previous proof-of-concept trial in individuals with HIV, pyridostigmine administration was shown to reduce T cell activation and proliferation, as well as increase the anti-inflammatory cytokine IL-10 and decrease the proinflammatory cytokine IFN-gamma.⁹

Additionally, in a Phase 2 pilot study (NCT00518154), pyridostigmine demonstrated its ability to increase CD4 counts in individuals with HIV who were virologically suppressed but had incomplete immunological response^.4,10

Half-life (T_1/2)

Following intravenous (IV) (4 mg) and oral (60 mg) administration of pyridostigmine bromide in healthy participants, the mean plasma elimination half-life of pyridostigmine was 200 minutes for the oral dose and 97 minutes for the IV dose.¹¹

Metabolism/Elimination

Pyridostigmine is metabolized via hydrolysis by cholinesterases, as well as by liver enzymes. It is excreted in the urine by tubular secretion as unchanged drug and as metabolites.¹¹

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT00518154

Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label pilot study was to evaluate whether adding pyridostigmine to ART could increase CD4 counts in individuals with suboptimal immunologic response despite viral suppression on ART.
Study Population: Participants were adults with HIV who had undetectable viral load levels while on ART for at least 2 years but had suboptimal immunologic response.¹⁰
Selected Study Results: Results published in Frontiers in Immunology (2017) found that the addition of pyridostigmine to ART led to a significant and long-lasting increase in circulating CD4 cells relative to baseline in participants who had incomplete immune reconstitution on ART.⁴

Study Identifier: NCT03312244

Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Phase: 2
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this study is to evaluate whether adding pyridostigmine to ART can increase CD4 counts in individuals with HIV who have viral suppression on ART.
Study Population: Participants are adults with HIV who have had undetectable viral load levels while on ART for the past 6 months.¹¹

Additionally, a Phase 1/2 trial (NCT04353778) is evaluating the use of low-dose pyridostigmine for reducing small intestinal bacterial overgrowth and signs of inflammation in adults with HIV. This study is currently recruiting participants.¹²

Adverse Events

Adverse Events

NCT00518154

In this Phase 2 pilot study, seven participants were enrolled to receive pyridostigmine as add-on therapy to ART. One of the seven participants withdrew from the trial prior to study completion for reasons unrelated to the study drug. No adverse events (AEs) related to pyridostigmine, including cardiovascular, respiratory, gastrointestinal, or genitourinary AEs, were identified during the study. Also, no cholinergic AEs affecting central nervous system (CNS) functions were observed.⁴

Additional AEs known to be associated with pyridostigmine are described in the FDA-approved Full Prescribing Information for Mestinon.⁵

Drug Interactions

Drug Interactions

Because pyridostigmine is mainly excreted renally as unchanged drug by active tubular secretion, some drug-drug interactions may potentially occur between pyridostigmine and coadministered HIV antiretrovirals that undergo active renal secretion.¹⁴

Additional known interactions between pyridostigmine and coadministered drugs may be described in the FDA-approved Full Prescribing Information for Mestinon.⁵

References

References

1. National Center for Biotechnology Information. PubChem compound summary for CID 7550, pyridostigmine bromide. Accessed August 25, 2023
2. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Study of the role of peripheral acetylcholinesterase inhibitor pyridostigmine as immunomodulators in a population of patients living with human immunodeficiency virus infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered April 1, 2017. NLM Identifier: NCT03312244. Accessed August 25, 2023
3. Čolović MB, Krstić DZ, Lazarevic-Pašti TD, Bondžic AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 2013;11(3):315-335. doi:10.2174/1570159X11311030006. Accessed August 25, 2023
4. Valdés-Ferrer SI, Crispín JC, Belaunzarán-Zamudio PF, et al. Add-on pyridostigmine enhances CD4+ T-cell recovery in HIV-1-infected immunological non-responders: a proof-of-concept study. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.01301. Accessed August 25, 2023
5. Bausch Health US, LLC. Mestinon: full prescribing information, December 2, 2020. DailyMed. Accessed August 25, 2023
6. Sandoz Inc. Regonol: full prescribing information, October 13, 2022. DailyMed. Accessed August 25, 2023
7. U.S. Food and Drug Administration (FDA) news release, dated February 5, 2003. FDA approves pyridostigmine bromide as pretreatment against nerve gas. Accessed August 25, 2023
8. Wang DW, Zhou RB, Yao YM. Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases. Chinese Journal of Traumatology (English Edition). 2009;12(6):355-364. doi:10.3760/cma.j.issn.1008-1275.2009.06.007. Accessed August 25, 2023
9. Valdés-Ferrer SI, Crispín JC, Belaunzarán PF, Cantú-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses. 2009;25(8):749-755. doi:10.1089/aid.2008.0257. Accessed August 25, 2023
10. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Pilot study of an ACh-E inhibitor upon immune activation markers in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) showing an incomplete immune response. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered August 17, 2007. NLM Identifier: NCT00518154. Accessed August 25, 2023
11. Bausch Health, Canada Inc. Mestinon and Mestinon-SR: product monograph. Health Canada. Accessed August 25, 2023
12. Icahn School of Medicine at Mount Sinai. Effects of vagal dysfunction on gastrointestinal and inflammatory pathways in HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered April 17, 2020. NLM Identifier: NCT04353778. Accessed August 25, 2023
13. University of Liverpool. HIV drug interactions: interaction checker. Accessed August 25, 2023

Last Reviewed: August 25, 2023