Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine

• Published in: Current research in pharmacology and drug discovery Vol. 3; p. 100112
• Main Authors: Luong, Thu-Lan T., Powers, Chelsea N., Reinhardt, Brian J., Weina, Peter J.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-01-2022; Elsevier
• Subjects: Cytochrome P450; Drug-drug interactions; Gefitinib; Losartan; Selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); Drug-drug interactions; Selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); Gefitinib; Cytochrome P450; Losartan
• ISSN: 2590-2571; 2590-2571
• DOI: 10.1016/j.crphar.2022.100112

To evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs).
In vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs.
The isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).
DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value ​= ​0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value ​= ​0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value ​= ​0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value ​= ​0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value ​= ​0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination.
The study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs.
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•In vitro hepatocytes assays can predict relevant drug-drug interactions (DDIs).•Proof-of concept data testing can provide a clear insight of multidrug regimen DDIs.•Classifying drugs as inhibitors/inducers alone cannot successfully identify DDIs.•Regimens requiring three or more drugs may cause significant DDIs (p-value < 0.05).•SSRI metabolism by human hepatocytes can be affected by gefitinib and losartan.