Development and validation of an UPLC-MS/MS method for the therapeutic drug monitoring of oral anti-hormonal drugs in oncology

Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r 2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CV abiraterone ≤ 9.72%; CV D4A ≤ 14.64%) and accurate (CV abiraterone 95.51-107.59%; CV D4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine. K E Y W O R D S abiraterone, bioanalytical method validation, D4A, therapeutic drug monitoring, UPLC-MS/MS 1 | INTRODUCTION Abiraterone [17-(3-pyridyl)-androsta-5,16-dien-3β-ol, C 24 H 31 NO], administered as the pro-drug abiraterone acetate, is an androgen synthesis inhibitor used to treat castration-resistant prostate cancer. The standard dose is 1,000 mg/day taken in fasted state in association with prednisone 10 mg/day (FDA, 2011). Clinical studies have provided evidence for the variable efficacy of treatment

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A quick UPLC–MS/MS method for therapeutic drug monitoring of abiraterone and delta(4)‐abiraterone in human plasma

Weiss

Furtado

Antunes

et al. 2020

“…Furthermore, it is relevant to investigate the stability when exposed to light as blood collection tubes are generally transparent. Nonetheless, stability at room temperature while exposed to light and in the dark was examined in only five papers (de Krou et al, ; Escudero‐Ortiz et al, ; Herbrink et al, ; Nijenhuis et al, ; van Nuland et al, ). The stability of processed samples was examined in 23 papers, either as re‐injection reproduciblity or as final extract stability.…”

Section: Stabilitymentioning

confidence: 99%

Bioanalytical LC–MS/MS validation of therapeutic drug monitoring assays in oncology

Nuland

Rosing

Schellens

et al. 2019

Therapeutic drug monitoring (TDM) has shown to benefit patients treated with drugs of many drug classes, among which is oncology. With an increasing demand for drug monitoring, new assays have to be developed and validated. Guidelines for bioanalytical validation issued by the European Medicines Agency and US Food and Drug Administration are applicable for clinical trials and toxicokinetic studies and demand fully validated bioanalytical methods to yield reliable results. However, for TDM assays a limited validation approach is suggested based on the intended use of these methods. This review presents an overview of publications that describe method validation of assays specifically designed for TDM. In addition to evaluating current practice, we provide recommendations that could serve as a guide for future validations of TDM assays.

Quality by design with design of experiments approach for development of a stability‐indicating LC method for enzalutamide and its impurities in soft gel dosage formulation

Katakam

Dongala²,

Ettaboina³

2021

A novel ultra‐performance liquid chromatographic (UPLC) method has been developed and approved for the quantitative determination of enzalutamide (ENZ) and its impurities in drug product dosage form by applying the quality by design with design of experiments approach. An efficient chromatographic separation was achieved on a Waters ACQUITY CSH C18 (100 × 2.1 mm × 1.7 μm) column in gradient elution mode. A mixture of potassium phosphate monobasic buffer and acetonitrile (10 mm, adjusted to pH 4.0 with 1% orthophosphoric acid) at a flow rate of 0.2 mL min−1 (column temperature at 40°C) under ultraviolet detection at 270 nm was used for quantitation. The peak resolution among ENZ and its impurities (Impurity‐1, Impurity‐2, Impurity‐3, Impurity‐4, Impurity‐5, Impurity‐6 and Impurity‐7) was greater than 2.5. Regression analysis confers an R2 value (correlation coefficient) higher than 0.999 for the active substance and impurities. The detection level for ENZ impurities was at a level below 0.015% (0.12 μg/mL). The accuracy levels for different compounds were close to 100%. The inter‐ and intra‐day precisions for ENZ and impurities were evaluated and their relative standard deviation (%) values were less than 3.5. Our results show that the UPLC–UV stability‐indicating method will be an essential tool that could determine the drug product’s impurities and be useful in regular quality control and stability studies of the ENZ drug product dosage form.