DRF-1042
目录号 : GC38774DRF-1042 是一种具有口服活性的喜树碱类似物,具有抑制 DNA 拓扑异构酶 I (DNA topoisomerase I) 的作用。DRF-1042 对一组人癌细胞株,包括多药耐药 (MDR)表型,显示出良好的抗癌活性。
Cas No.:200619-13-2
Sample solution is provided at 25 µL, 10mM.
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DRF-1042 is an orally active derivative of Camptothecin. DRF-1042 acts to inhibit DNA topoisomerase I. DRF-1042 shows good anticancer activity against a panel of human cancer cell lines including multi-drug resistance (MDR) phenotype[1][2].
DRF-1042 demonstrates superior lactone stability and good in vitro anticancer activity against a panel of human cancer cell lines including multi-drug resistance (MDR) phenotype[2].
In clonogenic assay against murine, canine and human bone marrow cells, DRF-1042 treatment shows less mylosupression that supports the possibility of protracted dose schedule in both experimental and clinical studies[2].
[1]. Chatterjee A, et al. Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novelcamptothecin analog, in refractory cancer patients in a bridging phase I study. J Clin Pharmacol. 2005 Apr;45(4):453-60. [2]. Sriram Rajagopal, et al. Preclinical evaluation of the anticancer activity of DRF-1042, a novel camptothecin analog targeting Topoisomerase-I. Published April 2004.
Cas No. | 200619-13-2 | SDF | |
Canonical SMILES | O=C1[C@](CC)(C2=C(C(N3C(C4=CC5=CC=CC=C5N=C4C3=C2)OCCO)=O)CO1)O | ||
分子式 | C22H20N2O6 | 分子量 | 408.4 |
溶解度 | DMSO: 50 mg/mL (122.43 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.4486 mL | 12.2429 mL | 24.4858 mL |
5 mM | 0.4897 mL | 2.4486 mL | 4.8972 mL |
10 mM | 0.2449 mL | 1.2243 mL | 2.4486 mL |
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Quantitative determination of DRF-1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics
Biomed Chromatogr 2003 Sep;17(6):385-90.PMID:13680849DOI:10.1002/bmc.253.
A simple and sensitive high-performance liquid chromatography (HPLC) method has been developed and validated for the determination of DRF-1042, a novel orally active camptothecin (CPT) analog, in human plasma. The sample preparation was a simple deproteinization with acidified methanol yielding almost 100% recovery of DRF-1042. An isocratic reverse-phase HPLC separation was developed on a Supelcosil-LC318 column (250 x 4.6 mm, 5 microm) with mobile phase consisting of 1% v/v triethylamine acetate, pH 5.5 and acetonitrile (80:20, v/v) at a fl ow rate of 1.0 mL/min. The eluate was monitored with a fluorescence detector set at excitation and emission wavelengths of 370 and 430 nm, respectively. The standard curves were linear (r(2) > 0.999) in the concentration ranges 5.0-2004 ng/mL. The lower limit of quantification (LLQ) of the assay was 5 ng/mL. The mean measured quality control (QC) concentrations (range 5 ng/mL to 40 microg/mL) deviated from the nominal concentrations in the range of -10.5-0.08 and -14.5-7.97%, inter- and intra-day, respectively. The inter- and intra-day precisions in the measurement of QC samples at four tested concentrations, were in the range 0.64-5.89% relative standard deviation (RSD) and 0.33-14.7% RSD, respectively. The method was found to be suitable for measurement of plasma concentrations above the calibration curve after serial dilutions. Stability of DRF-1042 was confirmed in a battery of studies, viz., on bench-top, in the auto-sampler, in the stock solutions, after four quick freeze-thaw cycles, up to one month at -20 degree C in human plasma and up to 2 months in the ex vivo samples. The method is simple, sensitive and reliable and has been successfully implemented to investigate the clinical pharmacokinetics of DRF-1042 in cancer patients in a phase I clinical trial.
Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study
J Clin Pharmacol 2005 Apr;45(4):453-60.PMID:15778426DOI:10.1177/0091270004270225.
The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).
Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study
J Clin Pharmacol 2004 Jul;44(7):723-36.PMID:15199077DOI:10.1177/0091270004265647.
The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.