CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients. Issue 3 (19th October 2022)

• Record Type: Journal Article
• Authors: Dalle Fratte, Chiara; Gagno, Sara; Roncato, Rossana; Polesel, Jerry; Zanchetta, Martina; Buzzo, Mauro; Posocco, Bianca; De Mattia, Elena; Borsatti, Rachele; Puglisi, Fabio; Foltran, Luisa; Guardascione, Michela; Buonadonna, Angela; Cecchin, Erika; Toffoli, Giuseppe
• Is Part Of: British journal of clinical pharmacology. Volume 89:Issue 3(2023)
• Page Start: 1089
• Page End: 1098
• Publication Date: 2022-10-19
• Subjects: CYP2C8 -- CYP2D6 -- GIST -- imatinib -- pharmacogenetics; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.15551
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: Patients on treatment with oral fixed dose imatinib are frequently under‐ or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib‐metabolizing cytochromes ( CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8 ) and imatinib and nor‐imatinib exposure. We also investigated the impact of concurrent drug–drug‐interactions (DDIs) on the association between GAS and imatinib exposure. Methods: Serial plasma samples were collected from 33 GIST patients treated with imatinib 400 mg daily within a prospective clinical trial. Imatinib and nor‐imatinib C trough were quantified by liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Genetic polymorphisms with a functional impact on imatinib‐metabolizing cytochromes were identified and a GAS was calculated for each gene. A DDI‐adjusted GAS was also generated. Results: Imatinib and nor‐imatinib C trough were measured in 161 plasma samples. CYP2D6 GAS and metabolizer status based on genotype were associated with imatinib and (imatinib + nor‐imatinib) C trough . CYP2D6 poor and intermediate metabolizers were predicted to have a lower nor‐imatinib/imatinib metabolic ratio than normal metabolizers (0.197 and 0.193 vs . 0.247, P = .0205), whereas CYP2C8 *3 carriers had a higher ratio than CYP2C8*1/*1 patients (0.263 vs . 0.201, P = .0220). CYP2C9 metabolizer status was inversely related to the metabolic ratio with an effect probably driven by the linkage disequilibrium between CYP2C9*2 and CYP2C8*3 . The CYP2D6 DDI‐adjusted GAS was still predictive of imatinib exposure. Conclusions: These findings highlight that CYP2D6 plays a major role in imatinib pharmacokinetics, but other players (i.e., CYP2C8 ) may influence imatinib exposure. These findings could drive the selection of patients more susceptible to imatinib under‐ or overexposure who could be candidates for personalized treatment and intensified monitoring strategies.