CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients

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.

Automated summary

This study investigated the association between gene activity score and imatinib exposure in GIST patients. The results showed that CYP2D6 plays a major role in imatinib pharmacokinetics, but other factors such as CYP2C8 may also influence the drug's exposure. These findings could help identify patients who are more susceptible to imatinib under- or overexposure for personalized treatment and monitoring strategies.