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Phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK‐333
Author(s) -
Okusaka Takuji,
Ueno Hideki,
Ikeda Masafumi,
Morizane Chigusa
Publication year - 2011
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2011.00800.x
Subject(s) - medicine , pharmacokinetics , postprandial , gastroenterology , dosing , cohort , maximum tolerated dose , urology , surgery , insulin
Aim: NIK‐333 (an acyclic retinoid) has been reported to prevent recurrence of hepatocellular carcinoma (HCC) in patients after curative treatment. This study was conducted to determine the maximum tolerated dose, dose‐limiting toxicities (DLT) and pharmacokinetics of NIK‐333 administrated p.o. at doses ranging 300–900 mg/day. Methods: Patients who were cancer‐free after percutaneous local ablation or surgical resection of HCC were enrolled. The total daily dose was administrated as a single dose (single‐dose stage) followed by a week of rest, and then in two equally divided doses administrated after breakfast and supper for 48 consecutive weeks (repeated‐dose stage). Results: No patients at the dose levels of 300 mg/day and 600 mg/day developed any DLT. At the final dose level of 900 mg/day, three of the nine patients developed grade 3 hypertension as a DLT. There were no significant difference values of maximum drug concentration (C max ) and log(C max ) between fasting and postprandial condition. In the repeated‐dose stage, there was no significant difference between the start and week 24 of NIK‐333 administration within any dose cohort in either the mean area under the blood concentration time curve (0–6 h) or the C max . NIK‐333 was well‐tolerated when administrated p.o. at doses of up to 600 mg/day for 48 weeks. Conclusion: Hypertension was noted as a DLT at the dose level of 900 mg/day, and this dose was considered to be inappropriate. The recommended dose for the phase II/III clinical trial is thought to be 300 mg/day and 600 mg/day.