PHASE-I STUDY OF THE ORALLY-ADMINISTERED BUTYRATE PRODRUG, TRIBUTYRIN, IN PATIENTS WITH SOLID TUMORS

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induc es differentiation and/or growth inhibition of a number of cell lines irt vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalatin g doses of tributyrin from 50 to 400 mg/kg/day. Doses were administere d p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses w ithout toxicity greater than grade 2. The time course of butyrate in p lasma was assessed on days 1 and 15 and after any dose escalation. Gra de 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 a nd 2 toxicities included diarrhea, headache, abdominal cramping, nause a, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alo pecia, odor, dysphoria, and clumsiness. There was no consistent increa se in hemoglobin F with tributyrin treatment. Peak plasma butyrate con centrations occurred between 0.25 and 3 h after dose, increased with d ose, and ranged from 0 to 0.45 mw. Peak concentrations did not increas e in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentratio ns near those effective in vitro (0.5-1 mM) were achieved, but butyrat e disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 m g/kg/day.