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/
Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors
Re: Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors
Introduction
Tyrosine kinases are a major family of proteins frequently dysregulated (either through somatic mutations or overexpression) in various cancers. Their critical role in the control of cancer phenotypes, coupled to the presence of suitable binding domains for small molecules, led to the development of many tyrosine kinase inhibitors (TKIs) as anti-cancer agents. As we are able to achieve a better control of the disease over the longer lifespan of a patient, these TKIs are now being considered as chronic medications as they are used over a long period of time. The increasing number of therapies has improved the prognosis for the disease but has augmented the challenge of evaluating patients for potential drug interactions during therapy 1.
Drug−drug interactions (DDIs) occur when a patient's pharmacological or clinical response to the drug is modified by administration or co-exposure to another drug. Pharmacokinetic interactions occur when one drug influences the pharmacokinetic processes such as absorption, distribution, metabolism and excretion, of another drug. Altered metabolism is among the most complex of these processes by which drug–drug interactions can occur, and induction or inhibition of hepatic enzymes by drugs are often implicated. The clinical consequences of enzyme induction or inhibition depend on the pharmacological and toxic effect of both the parent drug and its metabolite(s). For example, if the parent compound is more active than its metabolite, inhibition of metabolism increases the exposure to the drug and also its therapeutic and/or toxic effects. However, if the parent compound is a pro-drug, inhibition of metabolism may result in a decrease in therapeutic efficacy. More recently, another paradigm of interaction arises when the metabolite is more toxic, and hence induction of metabolism down this pathway can exacerbate toxicity.
“A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug. ... Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract.”
Tyrosine kinases are a major family of proteins frequently dysregulated (either through somatic mutations or overexpression) in various cancers. Their critical role in the control of cancer phenotypes, coupled to the presence of suitable binding domains for small molecules, led to the development of many tyrosine kinase inhibitors (TKIs) as anti-cancer agents. As we are able to achieve a better control of the disease over the longer lifespan of a patient, these TKIs are now being considered as chronic medications as they are used over a long period of time. The increasing number of therapies has improved the prognosis for the disease but has augmented the challenge of evaluating patients for potential drug interactions during therapy 1.
Drug−drug interactions (DDIs) occur when a patient's pharmacological or clinical response to the drug is modified by administration or co-exposure to another drug. Pharmacokinetic interactions occur when one drug influences the pharmacokinetic processes such as absorption, distribution, metabolism and excretion, of another drug. Altered metabolism is among the most complex of these processes by which drug–drug interactions can occur, and induction or inhibition of hepatic enzymes by drugs are often implicated. The clinical consequences of enzyme induction or inhibition depend on the pharmacological and toxic effect of both the parent drug and its metabolite(s). For example, if the parent compound is more active than its metabolite, inhibition of metabolism increases the exposure to the drug and also its therapeutic and/or toxic effects. However, if the parent compound is a pro-drug, inhibition of metabolism may result in a decrease in therapeutic efficacy. More recently, another paradigm of interaction arises when the metabolite is more toxic, and hence induction of metabolism down this pathway can exacerbate toxicity.
“A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug. ... Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract.”
Debbie
The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects
Am Fam Physician. 2007 Aug 1;76(3):391-396.
“Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.”
https://www.aafp.org/afp/2007/0801/p391.html
“Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.”
https://www.aafp.org/afp/2007/0801/p391.html
Last edited by D.ap on Sat Dec 29, 2018 10:36 pm, edited 1 time in total.
Debbie
The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects
“Genotype Testing
Jump to section +
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”
Jump to section +
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”
Debbie
Get to Know an Enzyme: CYP3A4
“In previous issues of Pharmacy Times, we have discussed the cytochrome P450 (CYP450) enzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6 (see www.PharmacyTimes.com/Drug Interactions). In the spirit of saving the best for last, in this issue, we will discuss the most important of all CYP450 enzymes: CYP3A4. It has been estimated that CYP3A4 metabolizes about half of all drugs on the market. Because many other commonly used drugs are moderate-to-potent inhibitors of CYP3A4, it is not surprising that drug toxicity of CYP3A4 substrates due to inhibition of CYP3A4 is relatively common.
CYP3A4 also is sensitive to enzyme induction, and a number of drugs are known to be CYP3A4 inducers. CYP3A4 inducers tend to lower plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of the substrate. This type of drug interaction is probably more frequent than commonly realized, because reduced drug effect may simply be attributed to lack of patient response.”
https://www.pharmacytimes.com/publicati ... 08-09-8687
CYP3A4 also is sensitive to enzyme induction, and a number of drugs are known to be CYP3A4 inducers. CYP3A4 inducers tend to lower plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of the substrate. This type of drug interaction is probably more frequent than commonly realized, because reduced drug effect may simply be attributed to lack of patient response.”
https://www.pharmacytimes.com/publicati ... 08-09-8687
Debbie
AVOIDING DRUG INTERACTIONS WITH YOUR TKI
Part 2
“Any medication has the potential of interacting with other substances, such as foods, beverages, other prescription drugs, supplements and over-the-counter medicines. One reason is that these substances need to be broken down by specialized enzymes in the liver and intestine, and various substances can have different effects on these enzymes.”
http://cml-iq.com/avoiding-drug-interactions-tki/
“Any medication has the potential of interacting with other substances, such as foods, beverages, other prescription drugs, supplements and over-the-counter medicines. One reason is that these substances need to be broken down by specialized enzymes in the liver and intestine, and various substances can have different effects on these enzymes.”
http://cml-iq.com/avoiding-drug-interactions-tki/
Debbie
AVOIDING DRUG INTERACTIONS WITH YOUR TKI
“In Part 1, we looked at how fruit juices can interfere with how your body metabolizes your TKI (tyrosine kinase inhibitor) medication, which may have an impact on the effectiveness of treatment or the frequency of side effects (see The grapefruit effect: what you need to know, CML-IQ, July 17, 2014).
Now let’s look at some of the drug interactions that can occur with TKIs (Gleevec, Tasigna, Sprycel).
As mentioned in Part 1, most medications are metabolized by a family of enzymes called the cytochrome P450 system. When you take a medication such as a TKI, certain cytochrome enzymes (called CYP3A4) bind to the TKI and eliminate it from the body. However, if another medication is in your body during this process, the other medication can either inhibit 3A4 enzyme action (e.g. by occupying the enzyme so it isn’t available to metabolize the TKI), or it can induce the enzyme (i.e. stimulate it so it is more active).”
Now let’s look at some of the drug interactions that can occur with TKIs (Gleevec, Tasigna, Sprycel).
As mentioned in Part 1, most medications are metabolized by a family of enzymes called the cytochrome P450 system. When you take a medication such as a TKI, certain cytochrome enzymes (called CYP3A4) bind to the TKI and eliminate it from the body. However, if another medication is in your body during this process, the other medication can either inhibit 3A4 enzyme action (e.g. by occupying the enzyme so it isn’t available to metabolize the TKI), or it can induce the enzyme (i.e. stimulate it so it is more active).”
Debbie
Re: Metabolism-related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors
“Reduced activity of CYP3A4 means that substrates of CYP3A4 are metabolized slower – leading to an increase in substrate concentration and an elevated potential for drug toxicity.Mar 10, 2018
pharmafactz.com › cyp3a4-enzyme-...
CYP3A4 Enzyme | Everything You Need to Know About CYP3A4!”
pharmafactz.com › cyp3a4-enzyme-...
CYP3A4 Enzyme | Everything You Need to Know About CYP3A4!”
Debbie
Clinically relevant drug interactions with multikinase inhibitors: a review
Clinically relevant drug interactions with multikinase inhibitors: a review
More current journal write up on multikinase inhibitors and drug reactions
Abstract
Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.
Keywords
cytochrome P450 enzyme, drug–drug interaction, drug transporters, gastric acid suppression, metabolism, multikinase inhibitor
https://journals.sagepub.com/doi/full/1 ... 5918818347
More current journal write up on multikinase inhibitors and drug reactions
Abstract
Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.
Keywords
cytochrome P450 enzyme, drug–drug interaction, drug transporters, gastric acid suppression, metabolism, multikinase inhibitor
https://journals.sagepub.com/doi/full/1 ... 5918818347
Debbie