Angelica herbal supplement AGN-Cogni.Q acute dose safety and pharmacokinetics (PK) dose-response in prostate cancer patients.

Abstract

372 Background: There are currently no FDA approved modalities for intercepting prostate cancer biochemical recurrence after surgery and pelvic radiotherapy to delay or prevent the need for subsequent androgen deprivation therapy. Preclinical modeling suggests Angelica gigas Nakai (AGN) root, its signature pyranocoumarins decursin D and decursinol angelate DA. and their hepatic metabolite decursinol DOH are potential novel modalities to address this unmet clinical need. Aside from our prior single dose PK study of AGN supplement Cogni.Q in healthy subjects, the acute dose safety and pyranocoumarin PK dose response patterns in cancer patients have not been studied. Methods: A single ascending dose (SAD) PK trial enrolled 12 prostate cancer patients (NCT05375539). Each subject was to receive 800, 1200, 1600, and 2000 mg of AGN-Cogni.Q at weekly intervals and assessed for safety by NCI CTCAE version 5.0, laboratory evaluations (CBC diff, CMP, 24 h) and EKG (5 h) vs pre-dose baseline. At each visit, pre-dose and PK blood was drawn hourly from 2 to7 h and at 24 h. Plasma D, DA, and DOH were quantified by LC-MS/MS. NK and T cells were immunophenotyped at baseline and 24 h after each dose as potential pharmacodynamic biomarkers. Results: Two subjects discontinued after the 800mg dose of AGN-Cogni.Q: Subject #005 experienced an adverse drug interaction with warfarin leading to exclusion of all warfarin users and Subject #010 due to preexisting neutropenia that worsened due to antidepressant med change. Five subjects received the full 4 doses, including Subject #009 with a non-specific ECG T-wave change 5 h after 2000mg dose and the highest DOH C max . Five subsequent subjects received 3 lower doses. No dose-limiting toxicities were observed. The DOH PK dose response was linear with a regression slope for C max of 1.05 and AUC 1.00. However, NK and T cell subtype frequencies in peripheral blood did not change vs. their respective baselines. Conclusions: The exposure PK metrics for DOH display a linear dose response. The AGN-warfarin adverse interaction and EKG safety signal provide critical exclusion criteria and dosage cap for future trials. Phase I/II study (NCT06600698) is ongoing to evaluate the long-term safety and efficacy in prostate cancer patients. Clinical trial information: NCT05375539 .