卡培他滨新型缓释制剂候选药物的0期临床试验。

A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine.

作者信息

Jacobs Bart A W, Meulenaar Jelte, Rosing Hilde, Pluim Dick, Tibben Matthijs M, de Vries Niels, Nuijen Bastiaan, Huitema Alwin D R, Beijnen Jos H, Schellens Jan H M, Marchetti Serena

机构信息

Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.

出版信息

Cancer Chemother Pharmacol. 2016 Jun;77(6):1201-7. doi: 10.1007/s00280-016-3035-5. Epub 2016 Apr 21.

DOI:10.1007/s00280-016-3035-5

PMID:27103124

Abstract

PURPOSE

To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.

METHODS

In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon(®) SR) in tablet matrix (0-5 % w/w) and coating (0-12 mg/cm(2)).

RESULTS

PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC0-2h, relative to AUC0-2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm(2), respectively. Corresponding AUC0-last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %).

CONCLUSION

Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm(2).

摘要

目的

研究几种卡培他滨候选缓释制剂在患者体内的药代动力学（PK）特征。

方法

在一项0期临床研究中，将几种卡培他滨口服候选缓释制剂的PK特征与市售即释（IR）片剂给药后的卡培他滨PK特征进行比较。第1天给予单剂量1000 mg IR制剂（两片500 mg片剂），第2天给予单剂量1000 mg卡培他滨候选缓释制剂（两片500 mg片剂）。卡培他滨候选缓释制剂在片剂基质（0 - 5% w/w）和包衣（0 - 12 mg/cm²）中的缓释辅料（聚维酮® SR）用量不同。

结果

研究了九种不同的卡培他滨候选缓释制剂的PK特征。片剂包衣似乎是卡培他滨缓释和片剂完整性的主要决定因素。相对于口服IR片剂后的AUC0 - 2h，包衣量为3和6 mg/cm²的候选缓释制剂的平均（±标准差）AUC0 - 2h分别为43.3%（±34.9%）和1.2%（±1.2%）。相应的AUC0 - last分别为93.6%（±40.2%）和44.0%（±5.4%）。