A phase I evaluation of the effect of curcumin on dose‐limiting toxicity and pharmacokinetics of irinotecan in participants with solid tumors

伊立替康 姜黄素 药代动力学 医学 药理学 毒性 置信区间 内科学 癌症 结直肠癌
作者
Olumide B. Gbolahan,Bert H. O’Neil,Autumn J. McRee,Hanna K. Sanoff,John K. Fallon,Philip C. Smith,Anastasia Ivanova,Dominic T. Moore,Julie B. Dumond,Gary Asher
出处
期刊:Clinical and Translational Science [Wiley]
卷期号:15 (5): 1304-1315 被引量:9
标识
DOI:10.1111/cts.13250
摘要

Curcumin inhibits UDP-glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m2 of i.v. infusion irinotecan on days 1 and 15 of a 28-day cycle, to determine the maximum tolerated dose (MTD) of PC. Thirteen participants received 4 g of PC (MTD) to assess the effect on the pharmacokinetic (PK) properties of irinotecan and its metabolites, SN-38 and SN-38G. Irinotecan, SN-38, and SN-38G exposure equivalence with and without curcumin was assessed using area under the plasma concentration-time curves from 0 to 6 h (AUC0-6h ). Safety assessments and disease responses were also evaluated. The combination of irinotecan and PC was well-tolerated. Because there was no dose limiting toxicity, the maximum dose administered (4 g) was defined as the recommended phase II dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan-associated toxicities. The objective response rate was 3/19 (22%, 95% confidence interval [CI]: 5-39%), median progression free survival and overall survival (n = 23) were 4 months (95% CI: 2.9-8.9 months) and 8.4 months (95% CI: 3.7 - not evaluable [NE]), respectively. Future studies are required to evaluate the efficacy of this combination.

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