Development and Validation of an HPLC Method for Analysis of Topotecan in Human Cerebrospinal Fluid and Its Application in Elimination Evaluation of Topotecan after Intraventricular Injection

SIMPLE SUMMARY: Intrathecal administration of anticancer drugs is an effective strategy to treat meningeal leukemia and lymphoma. Topotecan is an anticancer drug, and its anticancer effect is expected via intrathecal administration. In this study, we developed a method to measure the concentration of topotecan in the cerebrospinal fluid (CSF) for clinical monitoring of personalized medicine. By controlling the unique structural feature of topotecan, a pH-dependent lactone ring-opening/closing reversible reaction, we established a simple high-performance liquid chromatography (HPLC) method to measure the total topotecan concentration in the CSF and confirmed that this method can be applied to clinical samples. In the present situation, wherein the concentrations were monitored, the disappearance of topotecan in the CSF was delayed, and signs of adverse effects were confirmed when a high concentration of topotecan was observed. ABSTRACT: Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs.