Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer’s disease

 

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Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer’s disease

• Gabriel L Ketron,
• Felix Grun,
• Joshua D Grill,
• Howard H Feldman,
• Robert A Rissman &
• Gregory J Brewer 

Alzheimer's Research & Therapy volume 17, Article number: 59 (2025) Cite this article

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Abstract

Background

Nicotinamide, a form of B3 vitamin, is an NAD⁺ precursor that reduces pTau₂₃₁ levels via histone deacetylase inhibition in murine models of Alzheimer’s disease (AD). A recent phase 2a randomized placebo-controlled trial tested high-dose oral nicotinamide for the treatment of early AD. While nicotinamide demonstrated good safety and tolerability, it did not significantly lower CSF pTau₂₃₁, the primary biomarker endpoint of the study. Characterization of nicotinamide’s pharmacokinetics and metabolites in the blood and CSF is needed.

Methods

In these post hoc, blinded analyses of plasma and CSF samples from the completed two-site placebo controlled randomized trial testing of 1500 mg PO BID oral nicotinamide, we used mass spectroscopy to measure nicotinamide and its inactive metabolite 1-methyl-nicotinamide in plasma at baseline, 6, and 12 months and in CSF at baseline and 12 months from 23 participants on drug and 24 on placebo.

Results

Pharmacokinetic analysis found mean 12 month plasma nicotinamide increased > 130-fold to 52 μM while mean methyl-nicotinamide increased > 600-fold to 91 μM in individuals receiving nicotinamide compared to those receiving placebo, whose levels were unchanged from baseline. However, CSF nicotinamide was only measurable in 6 of the 19 available participants (32%) (mean increase of at least 147-fold to 18 μM). These CSF nicotinamide concentrations were 66% of their plasma levels, indicating good CNS bioavailability in only some participants. In contrast to CSF nicotinamide, more treated participants had higher CSF methyl-nicotinamide (n = 9, 43 μM), suggesting high-dosage nicotinamide was sufficient to pass the blood–brain barrier, but 13 of 19 were metabolically inactivated. Treatment favorably decreased mean pTau₂₃₁ levels by 34% in those six participants with elevated CSF levels of nicotinamide, compared to 3% elevation in participants who did not have elevated CSF nicotinamide, and a 3% decrease for placebo. No such relationships were observed for total tau, pTau₁₈₁, or amyloid beta biomarkers.

Conclusions

Our findings suggest that oral administration markedly increased mean plasma nicotinamide levels, however CSF levels were below quantitation in a majority of participants and there was extensive metabolic inactivation to methyl-nicotinamide. Both the bioavailability and rapid metabolic methylation need to be addressed if nicotinamide is further developed as a potential intervention for AD.

Trial registration

NCT03061474, last updated 2023–10-17. https://clinicaltrials.gov/study/NCT03061474.

Background

Nicotinamide serves as a co-enzyme precursor to NAD⁺ and NADH for cellular oxidation–reduction reactions. Inhibition of class III histone deacetylases (HDAC Sirtuins) affects numerous therapeutic pathways including inducing PI3k, MAPK/ERK42/44, cAMP and NAD⁺ production pathways, associated with neuronal survival, autophagy, neuroplasticity and lower oxidative stress [1, 2]. In mouse models of Alzheimer’s disease (AD), nicotinamide improved cognitive function while lowering Aβ and soluble p-tau isoforms [1, 2]. In these studies, nicotinamide in the drinking water reduced pTau₂₃₁ in immunostained brain sections [1]. Sirt1 knockdown produced a similar effect suggesting nicotinamide inhibited the Sirt1 deacetylase. Nicotinamide also promotes NAD⁺ dependent sirtuin activity through increased NAD⁺ production.

Oral nicotinamide is absorbed in the small intestine and encounters some first pass metabolism in liver to inactive N-methyl-nicotinamide. Blood concentrations are also lowered by kidney filtration that may affect CNS bioavailability. For oral nicotinamide to be CNS active, it must penetrate the blood brain barrier without being inactivated [3]. Some reports indicate nicotinamide is transported across the blood brain barrier bidirectionally with non-saturable capacity [3], probably due to rapid phosphorylation. The phosphorylation of nicotinamide is mediated by nicotinamide phosphoribosyl transferase to make nicotinamide mononucleotide, which is rapidly converted by nicotinamide mononucleotide adenylyl transferase into NAD⁺ in the “two-step salvage pathway” [4]. NAD⁺ is reduced to NADH by dehydrogenases in the mitochondrial TCA cycle and oxidized back to NAD⁺ in the electron transport chain. Lastly, Sirt1, PARP and CD38 enzymes cut NAD⁺ by glycohydrolysis into nicotinamide and ADP-ribose [5]. Consumption and degradation pathways of nicotinamide in the gut microbiome, intestines, blood, and liver complicate drug delivery to the brain. Importantly, nicotinamide inhibition of sirtuins in cells is limited by its metabolism to 1-methyl-nicotinamide (methyl-nicotinamide hereafter) by nicotinamide N-methyl transferase [6]. These preclinical studies suggested a potential role for treating bioenergetic or acetylation deficits in AD and motivated a phase 2a proof-of-concept clinical trial.

The Nicotinamide as an Early AD Treatment (NEAT) study tested high-dose (1500 mg PO BID) oral nicotinamide in participants with Mild Cognitive Impairment (MCI) or mild dementia in whom a biomarker signature confirmed a diagnosis of AD. The primary outcome of the trial was change in CSF pTau₂₃₁ [7]. Soluble varieties of phosphorylated tau (pTau) at specific epitopes such as threonine 231 (pTau₂₃₁) and threonine 181 (pTau₁₈₁) are established markers of AD pathology in brain and serve as early biomarkers in the CSF [8].

In the NEAT trial, nicotinamide treatment of participants with MCI and mild AD dementia did not significantly reduce CSF pTau₂₃₁ compared to placebo [7]. There were non-significant trends toward reduced change in CSF pTau₁₈₁ and total tau with nicotinamide treatment. In the current study, we undertook post hoc analysis of nicotinamide pharmacokinetics (PK), pharmacodynamic (PD) metabolic inactivation to methyl-nicotinamide, and the association between nicotinamide concentration change and pTau₂₃₁ concentration changes using samples from the NEAT trial. These analyses were undertaken to address whether there were sufficient levels in plasma and CSF with this oral nicotinamide dosage in this study population over the 48-week treatment period. Furthermore, the PK/PD relationship of plasma and CSF levels of both nicotinamide and methyl metabolite were evaluated with change in pTau₂₃₁ and pTau₁₈₁ concentrations, and other Aβ biomarkers. To measure these metabolite concentrations, and the concentrations of various break-down products, we conducted a Liquid Chromatography Mass Spectrometry (LC/MS) study of all NEAT participant samples.

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