A Rapid and Sensitive UPLC-MS/MS Method for Quantifying Capmatinib in Human Liver Microsomes: Evaluation of Metabolic Stability by In Silico and In Vitro Analysis

Abstract

Capmatinib (CMB) is an orally bioavailable mesenchymal–epithelial transition (MET) inhibitor approved by the US-FDA to treat metastatic non-small cell lung cancer (NSCLC) patients, with MET exon 14 skipping mutation. The current study aimed to establish a specific, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analytical method for quantifying CMB in human liver microsomes (HLMs), with therapeutic implications for assessing metabolic stability. Validation of the UPLC-MS/MS analytical method in the HLMs was performed using selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, stability, and matrix effects according to the guidelines for bio-analytical method validation of the US-FDA. CMB was ionized by positive electrospray ionization (ESI) as the ionization source and analysed using multiple reaction monitoring (MRM) as the mass analyser mode. CMB and pemigatinib (PMT) were resolved on the C18 column, with an isocratic mobile phase. The CMB calibration curve showed linearity in the concentration range of 1–3000 ng/mL. The intra- and inter-day accuracy and precision were −7.67–4.48% and 0.46–6.99%, respectively. The lower limit of quantification (LLOQ) of 0.94 ng/mL confirmed the sensitivity of the UPLC-MS/MS analytical method. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of CMB were 61.85 mL/min/kg and 13.11 min, respectively. CMB showed a high extraction ratio. The present study is the first to develop, establish, and standardize UPLC-MS/MS for the purpose of quantifying and evaluating the metabolic stability of CMB.

A Sensitive, Green, and Fast LC–MS/MS Analytical Method for the Quantification of Ribociclib: Evaluation of the Metabolic Stability in HLMs

“…The t 1/2 and Cl int of RCB were determined using an in vitro t 1/2 technique based on the well-stirred model, a widely employed model in drug metabolism studies due to its straightforward nature [19,20]. The intermediate metabolic rate of RCB was shown to have a moderate duration of action and low bioavailability in vivo, as reported in previous studies [21][22][23][24][25].…”

An LC–MS/MS Analytical Method for Quantifying Tepotinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

“…Using the scoring published by McNaney et al [36], it is proposed that TEP has an intermediate clearance ratio character. By using other in silico software (the simulation and Cloe PK software programs; Framingham, MA, USA), these results could also be used to predict the in vivo TEP pharmacokinetics [40,41].…”

An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

“…Because of its intrinsic simplicity, this specific model is frequently used in studies pertaining to drug metabolism. According to earlier research [16][17][18][19], the ACB showed a moderate metabolism rate, which led to a favorable in vivo bioavailability and a moderate duration of action. The small extraction ratio of ACB was discovered to be in line with the frequently advised regular dosage of ACB (100 mg), which should be given twice daily to patients diagnosed with B-cell malignancies [20].…”