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LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome.
J Pharm Biomed Anal. 2023 May 10; 228:115316.JP

Abstract

Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scarce for both molecules and a pharmacokinetically guided approach could help reaching eucortisolism more rapidly. We aimed to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ODT and MTP in human plasma. After addition of isotopically labeled internal standard (IS), plasma pretreatment consisted in protein precipitation with acetonitrile including 1% formic acid (v/v). Chromatographic separation was performed on Kinetex® HILIC (4.6 × 50 mm; 2.6 µm) analytical column with an isocratic elution during the 2.0-min run time. The method was linear from 0.5 to 250 ng/mL for ODT and from 2.5 to 1250 ng/mL for MTP. Intra- and inter-assay precisions were < 7.2%, with an accuracy ranging from 95.9% to 114.9%. The IS-normalized matrix effect ranged from 106.0% to 123.0% (ODT) and from 107.0% to 123.0% (MTP) and the range of the IS-normalized extraction recovery was 84.0-101.0% for ODT and 87.0-101.0% for MTP. The LC-MS/MS method was successfully applied in patients' plasma samples (n = 36), trough concentration of ODT and MTP ranged from 2.7 ng/mL to 8.2 ng/mL and from 10.8 ng/mL to 27.8 ng/mL, respectively. Incurred sample reanalysis exhibits less than 14% difference between the first and the second analysis for both drugs. This accurate and precise method, meeting all validation criteria, can therefore be used for plasma drug monitoring of ODT and MTP within the dose-titration period.

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Authors+Show Affiliations

Balakirouchenane D
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; Université Paris Cité, UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, CARPEM, 75006 Paris, France. Electronic address: davidbalak3@gmail.com.
Vasseur A
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.
Bonnet-Serrano F
Hormonal Biology Laboratory, Cochin Hospital, AP-HP, 75014 Paris, France; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, 75006 Paris, France.
Choi M
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.
Khoudour N
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.
Puszkiel A
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; Université Paris Cité, INSERM UMR-S1144, Faculty of Pharmacy, 75006 Paris, France.
Groussin L
Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, 75006 Paris, France; Department of Endocrinology, Cochin Hospital, AP-HP, 75014 Paris, France.
Vidal M
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; Université Paris Cité, UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, CARPEM, 75006 Paris, France.
Declèves X
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; Université Paris Cité, INSERM UMR-S1144, Faculty of Pharmacy, 75006 Paris, France.
Bertherat J
Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, 75006 Paris, France; Department of Endocrinology, Cochin Hospital, AP-HP, 75014 Paris, France.
Blanchet B
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; Université Paris Cité, UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, CARPEM, 75006 Paris, France.

MeSH

HumansChromatography, LiquidMetyraponeTandem Mass SpectrometryCushing Syndrome

Pub Type(s)

Journal Article

Language

eng

PubMed ID

36868030

Citation

Balakirouchenane, David, et al. "LC-MS/MS Method for Simultaneous Quantification of Osilodrostat and Metyrapone in Human Plasma From Patients Treated for Cushing's Syndrome." Journal of Pharmaceutical and Biomedical Analysis, vol. 228, 2023, p. 115316.
Balakirouchenane D, Vasseur A, Bonnet-Serrano F, et al. LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome. J Pharm Biomed Anal. 2023;228:115316.
Balakirouchenane, D., Vasseur, A., Bonnet-Serrano, F., Choi, M., Khoudour, N., Puszkiel, A., Groussin, L., Vidal, M., Declèves, X., Bertherat, J., & Blanchet, B. (2023). LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome. Journal of Pharmaceutical and Biomedical Analysis, 228, 115316. https://doi.org/10.1016/j.jpba.2023.115316
Balakirouchenane D, et al. LC-MS/MS Method for Simultaneous Quantification of Osilodrostat and Metyrapone in Human Plasma From Patients Treated for Cushing's Syndrome. J Pharm Biomed Anal. 2023 May 10;228:115316. PubMed PMID: 36868030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing's Syndrome. AU - Balakirouchenane,David, AU - Vasseur,Axelle, AU - Bonnet-Serrano,Fidéline, AU - Choi,Minna, AU - Khoudour,Nihel, AU - Puszkiel,Alicja, AU - Groussin,Lionel, AU - Vidal,Michel, AU - Declèves,Xavier, AU - Bertherat,Jérôme, AU - Blanchet,Benoit, Y1 - 2023/02/25/ PY - 2023/01/04/received PY - 2023/02/13/revised PY - 2023/02/23/accepted PY - 2023/3/31/medline PY - 2023/3/4/pubmed PY - 2023/3/3/entrez KW - Cushing’s syndrome KW - LC-MS/MS KW - Metyrapone KW - Osilodrostat KW - Pharmacokinetics KW - Therapeutic drug monitoring SP - 115316 EP - 115316 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 228 N2 - Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scarce for both molecules and a pharmacokinetically guided approach could help reaching eucortisolism more rapidly. We aimed to develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ODT and MTP in human plasma. After addition of isotopically labeled internal standard (IS), plasma pretreatment consisted in protein precipitation with acetonitrile including 1% formic acid (v/v). Chromatographic separation was performed on Kinetex® HILIC (4.6 × 50 mm; 2.6 µm) analytical column with an isocratic elution during the 2.0-min run time. The method was linear from 0.5 to 250 ng/mL for ODT and from 2.5 to 1250 ng/mL for MTP. Intra- and inter-assay precisions were < 7.2%, with an accuracy ranging from 95.9% to 114.9%. The IS-normalized matrix effect ranged from 106.0% to 123.0% (ODT) and from 107.0% to 123.0% (MTP) and the range of the IS-normalized extraction recovery was 84.0-101.0% for ODT and 87.0-101.0% for MTP. The LC-MS/MS method was successfully applied in patients' plasma samples (n = 36), trough concentration of ODT and MTP ranged from 2.7 ng/mL to 8.2 ng/mL and from 10.8 ng/mL to 27.8 ng/mL, respectively. Incurred sample reanalysis exhibits less than 14% difference between the first and the second analysis for both drugs. This accurate and precise method, meeting all validation criteria, can therefore be used for plasma drug monitoring of ODT and MTP within the dose-titration period. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/36868030/LC_MS/MS_method_for_simultaneous_quantification_of_osilodrostat_and_metyrapone_in_human_plasma_from_patients_treated_for_Cushing's_Syndrome_ DB - PRIME DP - Unbound Medicine ER -

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