PB, an aromatic fatty acid, demonstrates potent differentiating effects on multiple tumor cell lines. PB has pleiotropic molecular effects at concentrations of 0.5 -2.5 mM in vitro. This study of thrice daily oral PB is ongoing with 28 patients enrolled (12 advanced prostate cancer (CA), 6 renal cell CA, 3 breast CA, 1 thyroid CA, 3 colon CA, 2 bladder). Dose escalation continued up to 45g/day. Compliance has been excellent, despite the oral formulation, with patients ingesting 16 -40 375mg tablets 3X a day. Pharmacokinetics were obtained after equivalent oral and IV doses prior to chronic dosing. Cmax and relative exposure, measured as AUC, for PB and its metabolites, phenylacetate (PA), and phenylacetylglutamine (PAG) follow: AUCoral /AUCiv Cmax (mmmol/L) Dose n PB PA PAG PB PA PAG 9g 3 0.76 1.01 1.08 719 161 220 18g 3 0.82 1.00 1.22 633 187 354 27g 2 1.01 1.64 0.99 2326 662 429 36g 1 0.53 0.82 1.16 1088 685 538 AUCoral /AUCiv for PAG equals the fraction of PB absorbed from the GI tract. The oral bioavailability of PB is less than the fraction of PB absorbed from the GI tract because of hepatic first pass metabolism. At higher doses, PB concentrations remain above 0.5 mmol/L (in vitro bioactive threshold) nearly 3 hours. Toxicity has been mild with fatigue and lethargy cited most frequently. Dose limiting toxicity has been noted at 45 g/day and has been neurocortical in nature, similar to our intravenous study. No measurable responses have been noted, yet 6 patients have had stable disease for 6 months. PSA has declined by >50% in 1 patient at 36g/day, and 4 patients have had PSA stabilization over 2-6 months. Overall, oral PB is well-tolerated, with in vitro bioactive concentrations being consistently achieved in vivo. The recommended Phase 2 dose is 36 g/day.
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