Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug.
OBJECTIVE
Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50-100 microM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 microM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.


METHODS
Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.


RESULTS
The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.


CONCLUSIONS
Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.
Edelman
Martin J
MJ
Division of Hematology/Oncology, University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA. medelman@umm.edu
Bauer
Kenneth
K
Khanwani
Shyam
S
Tait
Nancy
N
Trepel
Jane
J
Karp
Judith
J
Nemieboka
Noble
N
Chung
Eun-Joo
EJ
Van Echo
David
D
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D016896:Treatment Outcome; D014280:Triglycerides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D014280:Triglycerides; C005830:tributyrin