Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug

被引:73
作者
Edelman, MJ
Bauer, K
Khanwani, S
Tait, N
Trepel, J
Karp, J
Nemieboka, N
Chung, EJ
Van Echo, D
机构
[1] Univ Maryland, Greenebaum Canc Ctr, Div Hematol Oncol, Baltimore, MD 21201 USA
[2] VA Maryland Hlth Care Syst, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA
[4] NCI, Med Oncol Clin Res Unit, Ctr Canc Res, Bethesda, MD 20892 USA
关键词
butyrate; histone deacetylase inhibitor; differentiating agent;
D O I
10.1007/s00280-003-0580-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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 muM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 muM. 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. Patients and 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 muM 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. Conclusion: Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.
引用
收藏
页码:439 / 444
页数:6
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