Thursday, June 8, 2023
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While we are well aware of the hazards of drug-drug interactions, there are several instances in which these interactions can be used to benefit patient care. We can use interactions to overcome induction, decrease pharmacokinetic variability, and reduce pill burden, all to our pharmacoeconomic advantage. We can space out the frequency of administration and improve intracellular pharmacokinetics. However, we are only beginning to understand the full potential of these mechanisms. During a symposium at the 41st ICAAC, investigators gathered to discuss the latest results and theoretical background in the beneficial use of drug-drug interactions. These interactions can involve cytochrome P450 metabolizing enzyme systems or transporter mechanisms using P-glycoprotein.
Dr. Joseph Bertino[1] of Bassett Healthcare, Cooperstown, New York, introduced his overview of drug disposition with a few definitions. The most relevant to this discussion was his view of pharmacogenomics, which he defined as the study of the hereditary basis for response differences to drugs. In the early days of humanity, our variable responses probably evolved from "plant-animal" warfare, when a variety of enzymes were adapted to destroy naturally occurring toxins in the environment. After tens of thousands of years, there is often great variability in enzyme number and activity from person to person. Because of these differences, one standard dose of a drug may not be suitable for everyone in a population.
Clinicians have long been aware of drug-drug interactions involving phase I reactions mediated by cytochrome (CYP) enzymes. For mammalian species, including us, P450 is the main CYP enzyme family. CYP enzymes are important for metabolizing drugs, helping humans adapt to the environment, activating some compounds and inactivating other toxins (or, unfortunately, for breaking them down into toxic metabolites). These enzymes are found throughout the body, not just in the liver.
For a given CYP enzyme -- for example, CYP2C9*1*2 -- the first "2" specifies the enzyme family (there are 14 known families in humans) , the "C" designates the sub-family (42 known in humans), and the "9" indicates the specific enzyme. The "*1*2" designates the "allele" pattern, or the gene variants present -- since we have 2 copies of every gene, the allele pattern will list 2 alleles. Usually, *1 is the normal or most common form of the gene, and *2 and higher indicate variations (Table 1).
"2" Enzyme family 14 known in humans "C" Enzyme subfamily 42 known in humans "9" Specific enzyme
"*1*2" Allele pattern Two alleles for every gene: -- *1 indicates normal or most common allele
-- *2 indicates a variant form
There are numerous other enzymes involved in phase II (conjugative) reactions, which can sometimes compensate for inadequate or inhibited CYP function. There are drug transporters such as P-glycoprotein (PGP), which can have a wide range of functions. For example, PGP assists in excretion of drugs into bile. PGP is found in the lining of epithelial cells of the gastrointestinal tract, where it functions as a barrier to transport. PGP can also be found in tumor cells, where it mediates drug resistance. It also functions elsewhere in the body, where it can pump drugs into the cerebrospinal fluid (CSF), for example.
Another transporter, organic anion transport protein (OATP), also functions in the gut as an efflux pump. It may surpass PGP in importance in this function under certain circumstances.
Genotyping involves investigating an individual's genetic code by the use of DNA and PCR-based testing. In other words, what specific drug metabolizing and transporting genes does a person have? In contrast, phenotyping investigates the manifestation of these genes. How do drugs, food, and other environmental factors affect metabolism and drug activity?
Several drugs can be used as "probes" to identify genetic differences in CYP enzyme activity. For instance, caffeine can be used to test CYP1A2 activity, dextromethorphan for CYP2A6, midazolam for CYP3A4/5, omeprazole for CYP2C19, and S-warfarin for CYP2C9.
Sometimes there is more than one form of the gene, or allele, that is common in the population, and this is called genetic polymorphism. Genetic polymorphism is considered to be present in a population when at least 1% of the people under study have a gene variant. Phenotypically, this polymorphism is seen when at least 1% of the population possesses a similar variation in how they metabolize or handle a drug.
Presence of a specific gene does not necessarily mean that it is active. Gene expression governs whether and how much enzyme is produced. Polymorphism in gene expression results in various scenarios, such as a deleted gene, which would result in no enzyme production and higher risk for toxicity. Another example is the presence of multiple copies of a gene, each of which could be unstable, normal, or altered. A person can also express a single gene that has higher metabolic capability, which could possibly make him or her less responsive to drugs. For CYP enzymes subject to polymorphism, most subjects will be extensive metabolizers (EM, the normal condition), some will be ultra-extensive metabolizers (UEM, or high metabolism), some will have reduced metabolism, and others will have no metabolism (PM, no enzyme or poor metabolizers). Genetics determines metabolism and transporters. Ethnic variability may exist (Table 2).
CYP Enzyme Population percent 2C19*2 or *3 Asians 13%-20% reduced activity or no active 2C19 2D6*2xN Ethiopians/Saudis 30% ultraextensive activity 2D6*10 Asians Up to 80% reduced activity 2D6*17 African-Americans 5% reduced activity
The expression of the effects of pharmacogenetics can vary with what one eats, drugs ingested, pollution, disease state, age, infectious diseases and cytokine production, gender (unusual), and menstrual cycle (rare).
Can we predict drug interactions? Inhibition reactions involve 3 mechanisms: rapidly reversible, slowly reversible, and irreversible. The result of enzyme inhibition can be increased drug exposure (ie, decreased metabolism), no change due to compensation by other mechanisms, or an increase in bioavailability (better absorption).
Induction occurs less frequently than inhibition but can change efficacy or safety by increasing enzyme synthesis or decreasing enzyme degradation. Induction tends to occur over time rather than immediately (10-14 days is typical), and de-induction also occurs over time (up to 14 days after removing the inducing agent). Interaction potential also depends on the pharmacokinetics of the substrate. Some agents auto-induce their own metabolism.
Dr. David Greenblatt[2] defined drug interactions as those of "victims" (such as terfenadine, astemizole, and cisapride) or "perpetrators" (such as mibefradil). He noted that absorptive interactions, which improve bioavailability, may be beneficial. Of the top 10 drugs in the United States (ranked by dollars, not volume), all are associated with drug-drug interactions, either as perpetrators or victims. While most drug combinations result in no interaction, clinically important interactions occur occasionally; those severe enough to warrant reducing the dose are rare. Given the possible number of potential drug-drug interactions, the actual number of serious ones is small.
Several drugs have incomplete oral bioavailability due to either presystemic extraction or metabolism in the liver (hepatic extraction) prior to reaching the general circulation. Options to increase absorption depend on an understanding of the mechanism of poor bioavailability, ie, is it a good substrate for CYP3A or a transporter such as PGP? For example, ketoconazole can increase the bioavailability of midazolam by a factor of 15 when midazolam is administered orally, but only by a factor of 5 when it is administered intravenously.[3] These data can be used to estimate how much of the interaction is due to liver metabolism and how much to gastrointestinal extraction.
Grapefruit juice contains furanocoumarin derivatives, which inhibit metabolism by CYP3A enzymes. For this interaction to occur, the substrate must be metabolized by this enzyme, given orally, and undergo presystemic extraction due to enteric CYP3A activity. The patient must express a significant amount of CYP3A in the gastrointestinal tract. If all this is true, then a beneficial drug-drug interaction may occur, which will increase the absorption of poorly bioavailable drugs and allow lower daily dosing.
Investigators in this field have been examining what factors regulate drug bioavailability, which drugs have the greatest degree of variable bioavailability, and which interventions can increase or decrease bioavailability. Dr. Angela Kashuba[4] of the University of North Carolina at Chapel Hill, reviewed CYP450 enzymes and metabolism interactions that improve systemic exposure to drugs (ie, bioavailability) (Table 3).
Factors affecting CYP enzyme activity CYP enzyme Nutrition and metabolism 1A2, 3A Smoking 1A2 Other environmental carcinogens and pollutants 1A2, 3A Disease 1A2, 2BC, 2C, 2D6, 3A Medications 1A2, 2BC, 2C, 2D6, 3A
CYP3A substrates include azole antifungals, macrolides, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors. There are a large number of CYP3A substrates with narrow therapeutic windows. For instance, several agents used to treat HIV infection can induce or inhibit CYP3A. How can we use this knowledge for our benefit? One example is inhibition of CYP metabolism, which can increase cyclosporine bioavailability. Cyclosporine pharmacokinetics vary greatly within the population, and even for a single patient. Patients with high dosing requirements for cyclosporine have a higher cost of therapy. However, ketoconazole can decrease the cyclosporine dose 50% to 80%.
Inhibition of CYP metabolism can also decrease the "pill burden" by improving absorption of protease inhibitors. Protease inhibitors have extensive variability in pharmacokinetics. Adding ritonavir in low dose to saquinavir can increase exposure of the latter and allow changing from thrice-daily to twice-daily dosing. Similarly, amprenavir can be changed to once-daily from twice-daily dosing with ritonavir coadministration.
The magnitude of benefit often depends on where the patient "starts"; that is, if low concentrations are achieved by therapy, the patient may have high enzyme activity and would benefit more from addition of an inhibitor. For instance, lopinavir metabolism is strongly inhibited by ritonavir. Consequently, concomitant oral administration results in a 77-fold increase in exposure to lopinavir. This beneficial interaction is exploited in the combination product Kaletra.[5]
Similarly, metabolic interactions can be used to overcome induction effects. Amprenavir exposure is decreased by 25% to 40% with concomitant efavirenz administration. This also can be overcome by adding ritonavir.[6] In general, variability of these agents is decreased by addition of ritonavir.
Dr. Keith Gallicano[7] of ABR Axelson BioPharma Research, Vancouver, British Columbia, Canada, discussed distribution interactions to improve clinical response.[5] Physiologic barriers to distribution are mediated by active transport, drug accumulation and sequestration (when influx is greater than efflux), and efflux membrane transport proteins. Huisman and associates[8] recently reviewed the clinical significance of PGP and the potential of transporter modulation. The question has been whether modulating transport proteins is physiologically acceptable and feasible.
Data have demonstrated discordant concentrations at select body sites vs what was predicted from simultaneous plasma concentrations. Such discrepancies may be a result of transport proteins, and these proteins may be targets amenable to intervention. For instance, loperimide, a potent opiate that does not produce opioid central nervous system effects at usual doses, is a substrate for PGP transport. When PGP was blocked with quinidine, respiratory depression occurred, which could not be explained by increased plasma loperamide concentrations. It was hypothesized that increased toxicity from PGP inhibition resulted from PGP blockade and increased CSF concentrations of loperimide.[9]
Other investigators found a disproportionate increase in the CSF concentration of ritonavir compared with plasma concentrations (178% increase vs 29% plasma) when administered with ketoconazole. This is consistent with ketoconazole's ability to inhibit transport of ritonavir out of the CSF.[10] Similar results were seen with saquinavir and ketoconazole.[10] Investigation of the CSF-to-plasma ratio for free indinavir has also not correlated with indexes of blood-brain barrier integrity, suggesting a clearance mechanism in addition to passive diffusion across the blood-CSF barrier. This is possibly PGP-mediated efflux.[11]
Penetration of antiretroviral agents into sites of the body that are HIV-1 reservoirs is important. If mechanisms of drug efflux out of cells via transporters could be blocked, efficacy might be enhanced. Investigation in 13 patients found that addition of low-dose ritonavir increases indinavir concentrations: In plasma and CSF, concentrations increased 2.4-fold as well, possibly due to inhibition of PGP transport.[12]
Overexpression of multidrug transporters significantly reduces accumulation of protease inhibitors in human lymphocytes. This is also an important site of virus replication. Cells that express PGP or multidrug resistance protein (MRP) transporters accumulate lower concentrations of protease inhibitors.[13] Initial work has suggested that modulation of these processes could result in enhanced clinical efficacy.[14]
The goal of this research is to improve treatment, either by improving absorption, decreasing metabolism, or reducing removal of drugs. The benefits are fewer pills, longer dosing periods, and reduced cost. So far, this research has been applied to only a few drugs, such as the ritonavir combinations for patients with HIV. However, continued research holds promise for further beneficial combinations.
