title: A novel approach for the simultaneous quantification of 18 small molecule kinase inhibitors in human plasma: A platform for optimised KI dosing.
abstract: Small molecule kinase inhibitors (KIs) are a rapidly expanding class of narrow therapeutic index antineoplastic drugs that exhibit substantial inter-individual variability in exposure. This manuscript describes a novel approach for the quantification of 18 KIs in plasma, providing a platform that is unparalleled in terms of scope for the assessment of KI therapeutic drug monitoring (TDM) and facilitating pharmacokinetic studies with KIs. Following the addition of a panel of four deuterated internal standards, plasma samples were prepared by solvent precipitation with acidified methanol. Analytes were separated on a Waters ACQUITY™ T3 HSS C18 analytical column (150×2.1mm, 1.8μm particle size) by linear gradient elution, with subsequent detection by time-of-flight mass spectrometry. Time-of-flight data were collected in wide pass mode, with selected ion (pseudo-MRM) spectra extracted at the precursor m/z of analytes in ESI+ mode. The analytical performance of this approach in terms of specificity, linearity, accuracy, precision range, quantification limit and detection limit meet all criteria for an analytical platform for the quantification of drugs. This approach was developed, validated and reported in accordance with the 2015 version of the FDA guidance for industry on 'analytical procedures are methods validation for drugs and biologics' facilitating direct application as a clinical trials platform.
authors: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, Australia. Electronic address: vand0307@flinders.edu.au.
authors: Madelé
authors: M
authors: van Dyk
authors: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, Australia; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.
authors: John O
authors: JO
authors: Miners
authors: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.
authors: Ganessan
authors: G
authors: Kichenadasse
authors: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.
authors: Ross A
authors: RA
authors: McKinnon
authors: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, Australia; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.
authors: Andrew
authors: A
authors: Rowland
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D057230:Limit of Detection; D016014:Linear Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
keywords: Pharmacokinetics; Small molecule kinase inhibitors; Therapeutic drug monitoring; Time-of-flight mass spectrometry; Ultraperformance liquid chromatography