Assay for the Quantification of Abemaciclib, Its Metabolites, and Olaparib in Human Plasma by Liquid Chromatography-tandem Mass Spectrometry

Overview

Journal J Pharm Biomed Anal

Specialty Chemistry

Date 2024 Oct 25

PMID 39454543

Authors

Kasey L Hill

Nicole L Abbott

Joo Young Na

Michelle Rudek

Kathleen Moore

Eudocia Q Lee

Mitch A Phelps

Affiliations

Soon will be listed here.

Abstract

An isotope-dilution bioanalytical assay for abemaciclib and its metabolites in combination with olaparib was developed and validated in human plasma K2 EDTA. For the quantitative assay, human plasma samples (or human plasma QC samples) were spiked with internal standard solution before a simple protein precipitation with methanol. The extract was injected onto a liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument where it was chromatographically separated by a polar end-capped reversed phase column and guard using gradient elution with water and methanol both modified with 0.2 % formic acid (v/v) as the mobile phases. The analytes and internal standards were measured by heated electrospray ionization (HESI) in positive polarity using selected reaction monitoring (SRM) on a triple quadrupole mass spectrometer. The assay was validated for linear ranges as follows: 0.4 - 1000 nM abemaciclib, 0.35 - 1000 nM M2 and M18, 0.5 - 1000 nM M20, and 0.75 - 1000 nM olaparib. The inter-day or between day precision for the quality controls (n = 18) was < 13 % and the accuracy was ± 12 %, for all analytes, including the lower limit of quantification (LLOQ). The intra-day or within day precision for the quality controls (n = 6) was ≤ 11 % and the accuracy was ± 12 % for low, mid, and high and < 19 % at LLOQ. The recovery in human plasma was determined to be between 92 % and 102 % for all analytes spanning the linear range. The validated, bioanalytical quantitative assay was designed to measure abemaciclib, its metabolites, and olaparib for pharmacokinetic evaluation of patients in clinical trials for breast, brain, and ovarian cancers.

References

Bruin M, de Vries N, Lucas L, Rosing H, Huitema A, Beijnen J . Development and validation of an integrated LC-MS/MS assay for therapeutic drug monitoring of five PARP-inhibitors. J Chromatogr B Analyt Technol Biomed Life Sci. 2020; 1138:121925. DOI: 10.1016/j.jchromb.2019.121925. View

Yonemori K, Tamura K, Kodaira M, Fujikawa K, Sagawa T, Esaki T . Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol. 2016; 78(3):525-31. PMC: 5010592. DOI: 10.1007/s00280-016-3106-7. View

Chigutsa E, Kambhampati S, Karen Sykes A, Posada M, van der Walt J, Turner P . Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2020; 9(9):523-533. PMC: 7499187. DOI: 10.1002/psp4.12544. View

Raub T, Wishart G, Kulanthaivel P, Staton B, Ajamie R, Sawada G . Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. Drug Metab Dispos. 2015; 43(9):1360-71. DOI: 10.1124/dmd.114.062745. View

Pilla Reddy V, Bui K, Scarfe G, Zhou D, Learoyd M . Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations. Clin Pharmacol Ther. 2018; 105(1):229-241. PMC: 6585620. DOI: 10.1002/cpt.1103. View

Stanislawiak-Rudowicz J, Karbownik A, Szkutnik-Fiedler D, Otto F, Grabowski T, Wolc A . Bidirectional pharmacokinetic drug interactions between olaparib and metformin. Cancer Chemother Pharmacol. 2023; 93(1):79-88. PMC: 10796410. DOI: 10.1007/s00280-023-04591-y. View

Patnaik A, Rosen L, Tolaney S, Tolcher A, Goldman J, Gandhi L . Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016; 6(7):740-53. DOI: 10.1158/2159-8290.CD-16-0095. View

Gelbert L, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena M . Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014; 32(5):825-37. PMC: 4169866. DOI: 10.1007/s10637-014-0120-7. View

Sparidans R, Martens I, Valkenburg-van Iersel L, den Hartigh J, Schellens J, Beijnen J . Liquid chromatography-tandem mass spectrometric assay for the PARP-1 inhibitor olaparib in combination with the nitrogen mustard melphalan in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879(21):1851-6. DOI: 10.1016/j.jchromb.2011.05.003. View

10.

Moore K, Colombo N, Scambia G, Kim B, Oaknin A, Friedlander M . Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018; 379(26):2495-2505. DOI: 10.1056/NEJMoa1810858. View

11.

Henning J, Boileau J, Peck L, McFarlane T . Clinical Considerations for the Integration of Adjuvant Olaparib into Practice for Early Breast Cancer: A Canadian Perspective. Curr Oncol. 2023; 30(8):7672-7691. PMC: 10453371. DOI: 10.3390/curroncol30080556. View

12.

Jolibois J, Schmitt A, Royer B . A simple and fast LC-MS/MS method for the routine measurement of cabozantinib, olaparib, palbociclib, pazopanib, sorafenib, sunitinib and its main active metabolite in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2019; 1132:121844. DOI: 10.1016/j.jchromb.2019.121844. View

13.

Martinez-Chavez A, Tibben M, de Jong K, Rosing H, Schinkel A, Beijnen J . Simultaneous quantification of abemaciclib and its active metabolites in human and mouse plasma by UHPLC-MS/MS. J Pharm Biomed Anal. 2021; 203:114225. DOI: 10.1016/j.jpba.2021.114225. View

14.

Sledge Jr G, Toi M, Neven P, Sohn J, Inoue K, Pivot X . MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017; 35(25):2875-2884. DOI: 10.1200/JCO.2017.73.7585. View

15.

Nijenhuis C, Lucas L, Rosing H, Schellens J, Beijnen J . Development and validation of a high-performance liquid chromatography-tandem mass spectrometry assay quantifying olaparib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2013; 940:121-5. DOI: 10.1016/j.jchromb.2013.09.020. View

16.

Groenland S, Martinez-Chavez A, van Dongen M, Beijnen J, Schinkel A, Huitema A . Clinical Pharmacokinetics and Pharmacodynamics of the Cyclin-Dependent Kinase 4 and 6 Inhibitors Palbociclib, Ribociclib, and Abemaciclib. Clin Pharmacokinet. 2020; 59(12):1501-1520. DOI: 10.1007/s40262-020-00930-x. View

17.

Fujiwara Y, Tamura K, Kondo S, Tanabe Y, Iwasa S, Shimomura A . Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer. Cancer Chemother Pharmacol. 2016; 78(2):281-8. DOI: 10.1007/s00280-016-3085-8. View

18.

Naz S, Sowers A, Choudhuri R, Wissler M, Gamson J, Mathias A . Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non-Small Cell Lung Cancer and . Clin Cancer Res. 2018; 24(16):3994-4005. PMC: 6137329. DOI: 10.1158/1078-0432.CCR-17-3575. View

19.

Wickremsinhe E, Lee L . Quantification of abemaciclib and metabolites: evolution of bioanalytical methods supporting a novel oncolytic agent. Bioanalysis. 2021; 13(9):711-724. DOI: 10.4155/bio-2021-0039. View

20.

Zhang J, Yang N, Ji D, Shen W, Li W, Han R . A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers. Target Oncol. 2021; 16(2):177-187. PMC: 7935732. DOI: 10.1007/s11523-020-00789-9. View