Short communicationAbsolute bioavailability studies of a new oral topotecan formulation in Chinese patients using UHPLC–MS/MS
Graphical abstract
Highlights
► The absolute bioavailability of a new oral topotecan formulation was estimated. ► The pharmacokinetics of oral topotecan in Chinese patients was first studied. ► A sensitive and time saving UPLC–MS/MS assay has been developed. ► The conversion between the lactone and carboxylate forms of topotecan was studied. ► The present study builds a bridge for further clinical research of oral topotecan.
Introduction
Topotecan [SK&F 104864, (S)-9-dimethylaminomethyl-10-hydroxy camptothecin] is a semi-synthetic water-soluble analog of camptothecin; it exists in a lactone form and a carboxylate form (Fig. 1) at physiological pH. As a specific inhibitor of topoisomerase I [1], topotecan interferes with the resealing of DNA single-strand breaks. It has shown good anticancer activity against a variety of human tumor types, including ovarian cancer [2], [3], cervical cancer [4], lung cancer [5], and malignant brain gliomas [6].
The intravenous (i.v.) formulation of topotecan received marketing approval for the treatment of ovarian cancer and relapsed small-cell lung cancer (SCLC) in 1996 and 1998, respectively, and the original capsule formulation (Hycamtin®) was recently approved (2007) for the treatment of relapsed SCLC. Xinze® is a new capsule formulation of topotecan being made in China which is similar to Hycamtin®. A bioequivalence study in dogs comparing Xinze® to Hycamtin® indicated 90% confidence intervals in the range of 0.80–1.29 for both AUC0−t and Cmax (unpublished observations), indicating that the new oral topotecan appears to be biologically equivalent to the prior formulation. Studies conducted in the Netherlands have reported the absolute bioavailability of topotecan to be 30–40% [7], [8]; it is not known whether the bioavailability in Chinese patients would also fall in this range. The objective of this study was to determine the absolute bioavailability and pharmacokinetics of this new oral topotecan formulation (Xinze®) in Chinese patients with SCLC.
Previously, high-performance liquid chromatography (HPLC) with fluorometric detection has been used to quantify topotecan in human plasma [9], [10], [11], [12]; topotecan levels can also be assessed with HPLC tandem mass spectrometry (HPLC–MS/MS)[13], [14]. To reach an optimized lower limit of quantification (LLOQ) for total topotecan and topotecan in the lactone form, we elected to use ultra high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) to establish our quantification in human plasma methodology for our bioavailability studies.
Section snippets
Reagents and materials
Topotecan hydrochloride (99.4% pure) was purchased from The National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). Acetonitrile and methanol (HPLC grade) were purchased from Fisher Scientific (Fair Lawn, NJ). Formic acid (HPLC grade) was purchased from Sigma–Aldrich (St. Louis, MO, USA). Ultra-pure water was prepared using a Milli-Q water purification system (Millipore Corp, Bedford, MA).
Instruments and analytical conditions
Chromatography was performed on an Acquity-UPLC® system (Waters
LC–MS/MS method development and sample preparation
We found that positive ionization was better than negative ionization for LC–MS/MS detection of topotecan in plasma. The CE in the LC–MS/MS mode was modulated to optimize the sensitivity, and the optimal values were found to be 29 and 34 eV for the lactone form and the carboxylate form, respectively.
As shown in Fig. 2, the properties of topotecan were closely related to the pH conditions. Topotecan samples were analyzed at moderately acidic and physiological pH on the basis of their mass spectra
Conclusion
Plasma concentration–time and pharmacokinetic analysis data were used to estimate the absolute bioavailability of topotecan in Chinese patients with SCLC. Although the sample size studied here was small, our findings indicate that oral topotecan administered at a dose of 1.5 mg/m2/d can produce bioavailability similar to that seen with i.v. administration. Hence, the present results indicate that oral topotecan treatment (Xinze®) can be used clinically at a safe dose in Chinese patients. The
Acknowledgements
The authors thank the patients and the physicians who participated in the study. The work was supported by the Ministry of Science and Technology of the People's Republic of China's and Beijing Municipal Science & Technology Commission, with the grant number 2012ZX09303012 and Z111102071011001, respectively.
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