Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations


Abstract
Drug−drug interactions (DDIs) occur when a patient's response to the drug is modified by administration or co-exposure to another drug. The main cytochrome P450 (CYP) enzyme, CYP3A4, is implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs). Therefore, there is a substantial potential for interaction between TKIs and other drugs that modulate the activity of this metabolic pathway. Cancer patients are susceptible to DDIs as they receive many medications, either for supportive care or for treatment of toxicity. Differences in DDI outcomes are generally negligible because of the wide therapeutic window of common drugs. However for anticancer agents, serious clinical consequences may occur from small changes in drug metabolism and pharmacokinetics. Therefore, the objective of this review is to highlight the current understanding of DDIs among TKIs, with a focus on metabolism, as well as to identify challenges in the prediction of DDIs and provide recommendations.

Keywords: cytochrome P450, drug−drug interactions, drug metabolism, pharmacokinetics, tyrosine kinase inhibitors



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309630/

The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects


“Pharmacogenetics
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One out of every 15 white or black persons may have an exaggerated response to standard doses of beta blockers (e.g., metoprolol [Lopressor]), or no response to the analgesic tramadol (Ultram). This is because drug metabolism via CYP450 enzymes exhibits genetic variability (polymorphism) that influences a patient's response to a particular drug.3“


https://www.aafp.org/afp/2007/0801/p391.html

The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects


“Pharmacogenetics
Jump to section +
One out of every 15 white or black persons may have an exaggerated response to standard doses of beta blockers (e.g., metoprolol [Lopressor]), or no response to the analgesic tramadol (Ultram). This is because drug metabolism via CYP450 enzymes exhibits genetic variability (polymorphism) that influences a patient's response to a particular drug.3“


https://www.aafp.org/afp/2007/0801/p391.html

Final paragraph

Genotype Testing

“Genotyping for CYP450 polymorphism has primarily been used for research purposes or clinical drug trials. Recently, the FDA approved the first genotype test designed for use by physicians to guide the selection of medications metabolized by CYP450 enzymes. The Amplichip CYP450 test is a DNA microarray that can detect 29 polymorphisms of CYP2D6 and two polymorphisms of CYP2C19 using a blood sample.33 Roche Diagnostics currently charges laboratories $500 per test, and most major insurance companies do not cover the cost.34 Although there is evidence of a link between adverse effects and polymorphisms coding for reduced CYP450 activity, large prospective clinical trials are needed to determine whether use of genotyping in clinical practice is cost-effective and improves clinical outcomes by preventing adverse drug effects or identifying poor responders.5,7,35,36”