Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment

Turković, Lu; Bočkor, Luka; Ekpenyong, Oscar; Silovski, Tajana; Lovrić, Mila; Crnković, Slaven; Nigović, Biljana; Sertić, Miranda

doi:10.3390/ph15050614

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Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment

⁴,

^5,6,

^7,8,

and

^1,*

Department of Pharmaceutical Analysis, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, 10000 Zagreb, Croatia

Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia

ADME & Discovery Toxicology, Merck & Co., Inc., South San Francisco, CA 94080, USA

⁴

Department of Oncology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia

⁵

Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia

⁶

Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, 10000 Zagreb, Croatia

⁷

Ludwig Boltzmann Institute for Lung and Vascular Research, Neue Stiftingtalstrasse 6/V, 8010 Graz, Austria

⁸

Division of Physiology, Medical University of Graz, 8010 Graz, Austria

Author to whom correspondence should be addressed.

Academic Editor: Maria Matilde Soares Duarte Marques

Pharmaceuticals 2022, 15(5), 614; https://doi.org/10.3390/ph15050614

Received: 5 April 2022 / Revised: 12 May 2022 / Accepted: 13 May 2022 / Published: 16 May 2022

(This article belongs to the Section Pharmacology)

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Abstract

Palbociclib, ribociclib and abemaciclib were recently approved as chemotherapeutic agents and are currently in the post-marketing surveillance phase. They are used in combination with aromatase inhibitors anastrozole and letrozole or antiestrogen fulvestrant for HR+, HER2− breast cancer treatment. Here, a novel bioanalytical LC-ESI-MS/MS method was developed for the quantitation of these six drugs in human plasma. The samples were prepared by simple protein precipitation followed by solvent evaporation. A Kinetex biphenyl column (150 × 4.6 mm, 2.6 µm) used for chromatographic analysis adequately resolved even the closely eluting aromatase inhibitors’ peaks. The mobile phase consisted of 0.1% formic acid in water and in ACN, in a linear gradient. An additional gradient step was added to eliminate the observed carry-over. The proposed method was fully validated in the relevant linear ranges covering the expected plasma concentrations of all six drugs (correlation coefficients between 0.9996 and 0.9931). The intra-day method precision (CV) ranged from 3.1% to 15%, while intra-day accuracy (%bias) was between −1.5% and 15.0%. The inter-day precision ranged from 1.6% to 14.9%, with accuracy between −14.3% and 14.6%, which is in accordance with the EMA and ICH guidelines on bioanalytical method validation. The method was successfully applied to samples from patients treated for HR+, HER2− breast cancer. View Full-Text

Keywords: CDK4/6 inhibitors; breast cancer; palbociclib; ribociclib; abemaciclib; anastrozole; letrozole; fulvestrant; therapeutic drug monitoring; LC-MS

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Turković, L.; Bočkor, L.; Ekpenyong, O.; Silovski, T.; Lovrić, M.; Crnković, S.; Nigović, B.; Sertić, M. Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment. Pharmaceuticals 2022, 15, 614. https://doi.org/10.3390/ph15050614

AMA Style

Turković L, Bočkor L, Ekpenyong O, Silovski T, Lovrić M, Crnković S, Nigović B, Sertić M. Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment. Pharmaceuticals. 2022; 15(5):614. https://doi.org/10.3390/ph15050614

Chicago/Turabian Style

Turković, Lu, Luka Bočkor, Oscar Ekpenyong, Tajana Silovski, Mila Lovrić, Slaven Crnković, Biljana Nigović, and Miranda Sertić. 2022. "Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment" Pharmaceuticals 15, no. 5: 614. https://doi.org/10.3390/ph15050614

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Development and Validation of a Novel LC-MS/MS Method for the Simultaneous Determination of Abemaciclib, Palbociclib, Ribociclib, Anastrozole, Letrozole, and Fulvestrant in Plasma Samples: A Prerequisite for Personalized Breast Cancer Treatment

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