Kidney Week

Abstract: SA-PO263

Health Effects (Renal) Of Extra Strength Avmacol (HEROES) Study: Results from the Pharmacokinetic Phase of a Randomized Double-Blind Placebo-Controlled Trial

Session Information

• Pharmacology: Kinetics, Genomics, Medication-Related Problems
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Wang, Yves T., University of Rochester Medical Center, Rochester, New York, United States

Yves T. Wang,

• Stewart, Allison J., University of Rochester Medical Center, Rochester, New York, United States

Allison J. Stewart,

• Sonawane, Sharvari A., University of Rochester Medical Center, Rochester, New York, United States

Sharvari A. Sonawane,

• Ghimirey, Rita, University of Rochester Medical Center, Rochester, New York, United States

Rita Ghimirey,

• Le, Thu H., University of Rochester Medical Center, Rochester, New York, United States

Thu H. Le,

Background

Increased oxidative stress is a major molecular underpinning of chronic kidney disease (CKD) progression. Decreases in the antioxidant enzyme glutathione-S-transferase μ-1 (GSTM1) due to a very common null gene variant have been shown to elevate oxidative stress and increase disease progression in animal and clinical studies. GSTM1 and many other antioxidant enzymes are regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. This pathway can be upregulated by sulforaphane (SFN), which can be obtained naturally from cruciferous vegetables such as broccoli. Commercially available SFN supplements provide much greater consistency in dosage compared to dietary intake, and mouse studies have shown oral supplementation to be protective in CKD. We hypothesize that daily intake of SFN – in the form of Avmacol Extra Strength (ES) – will decrease CKD progression rate and decrease markers of oxidative stress and inflammation. We will test the safety, tolerability, and efficacy of Avmacol ES taken daily for 6 months in CKD Stages 3-4 in a randomized, double-blind, placebo controlled clinical trial.

Methods

A pharmacokinetic (PK) study was first performed to establish an optimal dose of Avmacol ES for CKD patients with eGFR of 25 – 45 mL/min/1.73m² to achieve similar peak concentrations and area under the curve (AUC) of plasma SFN observed in non-CKD patients. Subjects were given 2, 4, or 6 tablets once daily for 7 days. Plasma was collected at 0-8 h after the last dose. SFN levels were measured by LC/MS/MS.

Results

Peak plasma concentration (C_max) was reached between 2-4 h (t_max) in subjects taking 4 tablets (average C_max: 120 nM, AUC8h: 824 nmol h/L, n = 4) and in those taking 2 tablets (average C_max: 85.1 nM, AUC8h: 581.4 nmol h/L, n=4). No C_max was observed in those taking 6 tablets during 8h, and gastrointestinal (GI) side effects (SE) were significant. Both 2 and 4 tablets daily were well tolerated with minimal GI SE.

Conclusion

In CKD 3-4, SFN t_max is delayed compared to the 1-2 h t_max reported in non-CKD subjects. Avmacol ES 4 tablets daily is well-tolerated with greater and more consistent C_max and AUC than 2 tablets daily and is being used in the on-going randomized phase.

Funding

• NIDDK Support – Nutramax (providing drug and placebo)