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Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals., Competing Interests: Compliance with ethical standards This study was conducted in full accordance with the International Conference on Harmonisation Good Clinical Practice Consolidated Guideline (E6) and any applicable national and local laws and regulations. Written informed consent was obtained from each patient before any study procedures or assessments were initiated. Potential conflicts of interest are as follows: CMN, JHB, ADRH, LL, MM-R, HR, and JHMS report employment from Netherlands Cancer Institute and research support from Teva Branded Pharmaceutical Products R&D during the conduction of the study; EH, LR-G, and PR Jr. report employment and stock options from Teva Branded Pharmaceutical Products R&D during the conduction of the study; OS and DH report employment from Teva Branded Pharmaceutical Products R&D during the conduction of the study; MM has nothing to disclose.

Omacetaxine mepesuccinate (hereafter called omacetaxine) is a modified cephalotaxine and is registered (Synribo(®)) for the treatment of adult patients with chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). To evaluate the pharmacokinetics of omacetaxine, sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for the quantification of omacetaxine and its inactive 4'-des-methyl (4'-DMHHT) and cephalotaxine metabolites in human plasma and urine were developed and validated. Since omacetaxine is mainly metabolised by esterases, the plasma samples were immediately stabilised after collection with an esterase inhibitor and stored at a nominal temperature of -80°C. Urine samples were stored at -80°C immediately after collection. Protein precipitation was applied as the sample pretreatment method for the plasma samples, and urine samples were processed using solid-phase extraction (SPE). For both assays, the dried and reconstituted extracts were injected on a XBridge BEH Phenyl column for analysis of all analytes. Gradient elution was applied with 0.1% formic acid in water and methanol as mobile phases. Analytes were ionised using a turbospray ionisation source in positive mode and detected with a triple quadrupole mass spectrometer. The validated plasma assay quantifies all analytes in the concentration range of 0.1-100ng/mL and the urine assay in the range of 0.1-50ng/mL. At all concentrations, the accuracies were within ±15% of the nominal concentrations and precisions were ≤15%. The developed methods have successfully been applied in a human mass balance study of omacetaxine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

New methods based on MEEKC coupling with field-amplified sample injection (FASI) induced by ACN were proposed for five isoquinoline alkaloids (berberine, palmatine, jatrorrhizine, sinomenine and homoharringtonine) in no salt and high salt sample solution (HS). For the separation of five isoquinoline alkaloids, a running buffer composed of 18 mM sodium cholate, 2.4% v/v butan-1-ol, 0.6% v/v ethyl acetate, 10% v/v (or 30% v/v) methanol and 87.0% v/v (or 67% v/v) 5 mM Na2B4O7~10 mM NaH2PO4 buffer (pH 7.5) was developed. In order to improve the sensitivity, FASI induced by ACN was applied to increase the detection sensitivity. The detection limit was found to be as low as 0.0002 microg/mL in no salt sample solution and 0.062 microg/mL in HS. The method has been applied for the analysis of human urine spiked with analytes, and the assay results were proved to be satisfactory, and also the determination of berberine in urine sample after oral administration berberine.

The metabolism of HH07A in the rat has been investigated by GC-MS. After oral administration of HH07A, the rat urine was passed through a macroporous XAD-2 resin column and eluted with methanol. The methanol extract was hydrolyzed with glucuronidase, extracted with dichloromethane and concentrated for TMS derivatization with GC-MS. The mass spectra of HH07A and its four metabolites as well as their derivatives were presented. The structures of the metabolites were proposed and the in vivo metabolic pathway of HH07A was given in Figure 6.

Clinical pharmacokinetics of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m2 (150 mu Ci) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total [3H]HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an alpha-half-life of 0.5 +/- 0.1 hours and a beta-half-life of 9.3 +/- 1.4 hours. The total clearance of HHT was 177.4 +/- 27.7 ml X hour-1 X kg-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 +/- 0.4 L X kg-1. Correspondingly, the total [3H]HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total 3H was 67.5 +/- 7.5 hours, 7.4 times longer; the total clearance was 30.9 +/- 3.1 ml X hour-1 X kg-1, 5.5 times slower; but the volume of distribution by area was 2.7 +/- 0.1 L X kg-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.