Managing Drug Interactions with Enzalutamide in Patients with Prostate Cancer: A Podcast

00:00:00: You are listening to an ADIS Journal podcast.

00:00:18: I'm Judith Bianco from Pfizer Inc.

00:00:20: And I'm Jesse Mack from Estellus Pharma.

00:00:23: We're both clinical pharmacists by training and your host for today's podcast on managing drug interactions with insolutamine and patients with prostate cancer.

00:00:31: Available in the Journal Drug Safety.

00:00:34: Editorial support for this podcast was provided by Jack Lau PhD at Impact Communication Partners and funded by Pfizer and Estellus Pharma.

00:00:43: The patient cases described in this podcast are fictional and do not represent actual events or a response from actual patients.

00:00:51: The authors develop fictional cases for educational purposes only.

00:00:54: In

00:00:56: this podcast, we're diving into the complex world of prostate cancer treatments and the risk of drug-drug interactions, a situation that can happen when patients take several concurrent medications for various comorbid conditions.

00:01:10: We're happy to have Dr.

00:01:12: Alicia Morgan from the Dana-Farber Cancer Institute and Dr.

00:01:16: Brooke Looney from the Vanderbilt University Medical Center to share their insights and expertise on this important topic.

00:01:22: Thank you both for joining.

00:01:24: Thank you so much, Jesse and Judith, for having me.

00:01:27: I'm so happy to be here.

00:01:29: Actually, I just want to share that I'm a GU medical oncologist with a focus for most of my patient care in prostate cancer.

00:01:35: And again, just very happy to be here.

00:01:39: Thank you, Jesse and Judith.

00:01:40: I'm thrilled to be here as well.

00:01:42: I am a clinical pharmacist with the Adult Outpatient Oncology Specialty Pharmacy at the Vanderbilt University Medical Center where my primary focuses on oral oncology medications and that ranges from access and affordability to patient education, monitoring, and outcomes research.

00:02:00: It's so great to talk with both of you again.

00:02:02: Let's take a minute and discuss why we're here and why this is so important for our listeners.

00:02:08: Prostate cancer is the second most diagnosed cancer in men worldwide following lung cancer.

00:02:14: In twenty twenty three alone, the United States saw approximately three hundred thousand new cases of prostate cancer, resulting in thirty five thousand deaths.

00:02:24: These numbers underscore the urgency to better understand and effectively manage this disease.

00:02:29: Not surprisingly, age is a known risk factor with the median age of diagnosis being sixty seven years old.

00:02:38: And as men age, they often contend with many health issues, leading to the concurrent use of multiple medications to manage these conditions, also known as polypharmacy.

00:02:48: This reliance on multiple medications poses additional challenges, particularly the heightened risk of drug-drug interactions or DDIs.

00:02:57: As such, there's a critical need to identify and address potential DDIs in these cases.

00:03:04: Drug interactions occur by way of various mechanisms, including both pharmacokinetic and pharmacodynamic interactions.

00:03:11: Even though it's important to consider the molecular and physiological basis for all types of DDIs, today we'll primarily be focusing on the metabolic and drug-transporter pharmacokinetic interactions.

00:03:23: These involve cytochrome P-Four-Fifty enzymes, or SIPs, and P-Glegopartines, or PEGPs.

00:03:31: SIPs are responsible for metabolizing approximately seventy-five percent of drugs in the liver.

00:03:36: When activated, the SIP enzymatic activity can be inductive or inhibitory, ultimately altering the plasma drug concentration and potentially modifying efficacy and or the adverse drug reaction occurrence.

00:03:50: So basically an induction of SIP enzymes could increase the metabolism of their substrates, resulting in reduced drug effects.

00:03:58: and SIP enzyme inhibition could lead to decreased drug metabolism, which could increase drug concentration and the risk for adverse effects.

00:04:07: This applies to drugs that are metabolized by the SIP enzymes.

00:04:11: Exactly.

00:04:12: And DDIs may also impact the metabolic conversion of prodrugs to their active metabolites by way of SIP enzymes.

00:04:21: In the case of a prodrug, SIP induction can increase production and or concentration of its active metabolite.

00:04:29: It's also possible for co-administered drugs to have DDIs that don't cause meaningful clinical outcomes.

00:04:35: This is observed when a drug is metabolized via several metabolic pathways involving different SIP enzymes and or PGP.

00:04:44: These scenarios can occur when co-administered drugs have a high therapeutic index or a wide range of concentrations at which the agent can remain effective without toxic effects.

00:04:56: However, the risk of adverse events due to DDI is more pronounced when medications with a narrow therapeutic index, such as warfarin or immunosuppressants, some examples include cyclosporin or serialimus, are co-am ministered with strong inducers of SIP enzymes.

00:05:14: Additionally, it is worth noting that the activity and expression levels of each SIP can vary significantly among individuals because of genetic differences.

00:05:23: For example, Gene duplication of SIP-II-D-VI, which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression.

00:05:35: It has also been suggested that patients who carry SIP-II-C-IX polymorphic alleles II and III are more susceptible to bleeding complications with warfarin treatment.

00:05:45: These are all important factors that healthcare professionals should consider when treating patients with different comorbid conditions in order to minimize if not avoid the risk of unintended DDIs.

00:05:58: Thank you, Judith.

00:05:59: Now let's delve into enzalutamide, a non-steroidal androgen receptor pathway inhibitor indicated for the treatment of men with castration resistant prostate cancer, metastatic castration sensitive prostate cancer, and non-metastatic castration sensitive prostate cancer with biochemical recurrence at a high risk for metastasis.

00:06:21: Enzalutamide is administered once daily as an oral medication at a hundred and sixty milligrams per day and patients receiving Enzalutamide for advanced prostate cancer should be undergoing testosterone suppression with androgen deprivation therapy either by receiving a gonadotropin releasing hormone or GNRH agonist or antagonist concurrently or they have had a bilateral orcheectomy.

00:06:46: Enzolutamide undergoes hepatic metabolism, primarily by SIPs III, IV, and II, CIII, to form an active desmethyl metabolite and an inactive carboxylic acid metabolite.

00:06:58: Enzolutamide

00:07:00: is metabolized by these SIP enzymes.

00:07:03: Jesse, could you also describe some of the effects enzolutamide has on a few notable SIPs?

00:07:09: Sure.

00:07:10: Enzalutamide is a moderate inducer of CYPs-II-C-IX and II-C-IX and a strong inducer of CYP-III-IV.

00:07:18: And because of that, Enzalutamide has the potential for DDIs when co-administered with a broad range of drugs that are CYP substrates due to induction of these important enzymes, resulting in possible loss of efficacy or increased risk of drug-related adverse events.

00:07:35: The potential impact of insolutomide on the metabolism and or bioavailability of other therapeutic agents will be discussed in more detail by our panel experts based on several patient case studies.

00:07:47: It's no surprise that prostate cancer, particularly in patients over sixty-five years of age, often coexist with myriad of comorbidities, including hypertension, high cholesterol, diabetes, cardiovascular diseases, chronic pain, depression, anxiety, and others.

00:08:04: As a result, these patients commonly find themselves juggling multiple medications alongside their prostate cancer treatments.

00:08:12: With all this in mind, we'd like to discuss the complicated question.

00:08:16: How do we navigate these potential interactions to ensure patient safety and treatment efficacy?

00:08:22: Let's talk to the experts and have both Drs.

00:08:25: Looney and Morgans walk us through a few hypothetical patient cases to help us understand the potential for drug-drug interactions with enzalutamide.

00:08:34: and discuss strategies or best practices to minimize the risk.

00:08:38: As noted at the beginning, these are fictional cases discussed in the podcast and they do not represent actual patient cases.

00:08:46: And we will start with Dr.

00:08:47: Looney.

00:08:48: The floor is yours.

00:08:50: Thank you Judith and Jesse for this opportunity to be here with Dr.

00:08:53: Morgan's and share my clinical experience and approach to managing a patient diagnosed with metastatic castration sensitive prostate cancer or CSPC.

00:09:02: John is sixty-nine years old and has a prior history of cardiovascular disease with a recent episode of deep vein thrombosis or DVT in his leg.

00:09:12: Now before we discuss John's treatment, can we talk about the significance of a prostate cancer patient with concurrent cardiovascular disease?

00:09:19: Sure, it's estimated that thirty percent of patients with prostate cancer have known cardiovascular risk factors such as obesity, diabetes, hypertension, and hyperlipidemia at the time of diagnosis.

00:09:32: And, seven point five percent of males age sixty to seventy nine years old, the group most frequently diagnosed with prostate cancer, have cardiovascular disease.

00:09:42: And currently, cardiovascular disease is the leading cause of death in patients with prostate cancer, accounting for approximately one in four deaths.

00:09:52: So this really solidifies the importance of being able to manage the drugs used to treat and or control these comorbidities and elderly patients with prostate cancer.

00:10:02: Now back to John.

00:10:03: What treatment is he receiving for his prostate cancer?

00:10:06: John is prescribed enzalutamide in combination with an oral GNRH antagonist, relucolyx, as his treatment for metastatic CSPC.

00:10:15: Prostate cancer requires a multifaceted approach to treatment.

00:10:19: and a majority of patients undergo treatment with enzolutamide plus androgen deprivation therapy, or ADT.

00:10:25: Injectable ADTs, such as luporlide, gocerellin, tryptorellin, and degorellics, aren't metabolized by hepatic SIPS and are not known to interact with enzolutamide.

00:10:38: For convenience, an increasing number of patients are turning to the oral GNRH antagonist, relucolix, which was shown in a clinical trial to be safe and effective when co-administered with enzolutamide.

00:10:48: with no dose adjustment required, even though relugalix is a substrate of SIP-III, SIP-II-C-III, and PGP.

00:10:58: And how is his cardiovascular disease being managed?

00:11:02: Given his prior episode of DVT, John is prescribed a pyxaban, a direct oral anticoagulant, or DOAC.

00:11:10: We know there are some concerns when prescribing enzolutamide with DOACs.

00:11:14: Are there any red flags to prescribing enzolutamide and relugalix for use concurrently with the pyxaban?

00:11:21: Yes, epixiband is subject to potential DDIs by dual inhibitors and inducers of CYP-IIIA IV and PGP.

00:11:29: And since enzolutamide is a strong CYP-IIIA IV inducer and a mild PGP inhibitor, it may result in a decrease in epixiband plasma concentration and exposure.

00:11:39: However, the effect of enzolutamide on the plasma concentration of epixiband isn't very clear because of the opposing CYP-IIIA IV and PGP interactions.

00:11:49: What's the best way then to proceed with epixaban or other drugs where the effects of co-administration aren't clear?

00:11:57: Based on the current prescribing information, co-administration of DOACs, including epixaban with enzalutamide, should be carefully monitored with possible changes to dosing to ensure that drug efficacy and safety are maintained.

00:12:11: As a standard practice, I would recommend that a thorough patient evaluation be conducted prior to DOAC initiation.

00:12:18: This should include assessment of baseline laboratory values, concomitant drug therapies, and co-morbidities.

00:12:25: Considering

00:12:26: the potential risks of

00:12:27: drug-drug interactions between enzalutamide and epixaban, are there other alternatives you would recommend for managing John's DVT?

00:12:36: Specifically,

00:12:37: would warfarin be a viable option?

00:12:40: Given that enzalutamide reduces warfarin's AUC by fifty-six percent and its CMAX by seventeen percent, Could this combination still be effective for John?

00:12:51: Warfarin is a substrate of CYP-II-C-IX and CYP-III-A-IV and has a narrow therapeutic index.

00:12:58: Since enzolutamide is a strong CYP-III-A-IV inducer and a moderate CYP-II-C-IX inducer, it also has the potential to decrease the effect of warfarin by decreasing its exposure.

00:13:10: I'd say that co-administration of enzolutamide and warfarin should be avoided if at all possible.

00:13:15: or additional INR monitoring should be conducted if co-administration of these two drugs is unavoidable.

00:13:21: We still have some other options.

00:13:23: There are DOACs that are minimally metabolized by SIP enzymes and are only subject to DDIs with inhibitors and inducers of PGP.

00:13:31: Two examples of these are Dabigatran and Adoxaban.

00:13:35: Since these two DOACs are minimally metabolized by SIP enzymes, what does that mean for their interactions with Enzalutamide?

00:13:43: Well, insolutamide has been reported to be a mild inhibitor of PGP, so there is potential for a DDI with these DOAX.

00:13:51: But there may be less of an interaction than we'd see with a pixabin, with the possible exception for patients with renal impairment.

00:13:57: Dosing of that bigotran and insolutamide should be based on the indication and level of renal dysfunction.

00:14:04: And I would highly recommend a consult with the pharmacist to assist with the appropriate dose reduction.

00:14:09: of the bigotran or to determine if another DOAC is warranted.

00:14:14: These are great insights.

00:14:15: Thank you so much, Dr.

00:14:16: Looney.

00:14:17: Now let's have Dr.

00:14:18: Morgan share a different case of an elderly gentleman undergoing active treatment with insolutomide for prostate cancer and receiving other medications concomitantly to manage his hypertension and high cholesterol.

00:14:30: Thanks, Jesse.

00:14:32: Let's start with some basics.

00:14:33: Dr.

00:14:34: Morgans, could you discuss the prevalence of high cholesterol and hypertension as risk factors for cardiovascular disease and prostate cancer patients?

00:14:42: Of course.

00:14:43: Echoing what Dr.

00:14:44: Looney mentioned earlier, cardiovascular disease is actually the most common cause of death in prostate cancer patients, with hypertension being one of the most common modifiable risk factors of cardiovascular disease.

00:14:56: It contributes to increase morbidity and mortality from heart failure, myocardial infarction, or MI.

00:15:02: arrhythmia and stroke.

00:15:04: Mortality associated with hypertension has been increasing, particularly among older adults.

00:15:08: This is the same population associated with higher overall incidence of malignancy and prostate cancer.

00:15:15: In this patient population, it's important to ensure adequate screening and treatment of high blood pressure, which can manifest for the first time or worsen as a result of cancer-directed therapy.

00:15:26: Thank you for that explanation.

00:15:27: Now let's dig into your patient case.

00:15:30: Bob is a seventy-one-year-old man diagnosed with high-risk biochemical recurrent non-metastatic prostate cancer.

00:15:36: He has a long history of poorly controlled hypertension and high cholesterol, which would put him at very high risk for cardiovascular disease.

00:15:45: Currently, he's on enzalutamide for his prostate cancer, varapamil for hypertension, and atorvastatin to reduce his elevated cholesterol.

00:15:53: For a patient like Bob, could you discuss the potential for drug-drug interactions between enzalutamide and medications like statins or calcium channel blockers?

00:16:01: Of course.

00:16:02: Enzalutamide is a strong CYP-IIIA-IV inducer, which can potentially reduce atorvastatin exposure, since atorvastatin is a substrate of CYP-IIIA-IV and the transporters PGP and BCRP.

00:16:15: So liver function and lipid levels should be carefully monitored when statins are co-administered with enzalutamide to assess their safety and efficacy.

00:16:23: And what would be your

00:16:24: approach to monitor lipid levels in a patient receiving a statin alongside enzalutamide?

00:16:30: I would coordinate with a patient's primary care physician or cardiologist to have them check a patient's lipid panel before starting statin therapy and every six to eight weeks to assess the treatment response.

00:16:40: I'd also consider working with those teams to adjust statin dosage levels during therapy if needed.

00:16:46: It's worth noting though that the atorvastatin prescribing information does not provide dose adjustment recommendations.

00:16:52: If lipid control is satisfactory with no evidence of adverse events, subsequent lipid monitoring can be done every four to six months.

00:17:00: So Dr.

00:17:00: Morgan's, what alternative would you take to manage Bob's high cholesterol?

00:17:05: Other types of statins such as patavastatin, pravastatin, and resuvastatin may be suitable alternatives for prostate cancer patients who take enzalutamide as these agents are minimally metabolized by CIPs and have no known basis for interactions with enzalutamide.

00:17:21: And now

00:17:21: how about the hypertensive agent that Bob was taking?

00:17:24: I would think that there might be the potential for drug interactions with calcium channel blockers since these agents are metabolized by CIP-III-IV.

00:17:32: That's correct.

00:17:33: Most of the commercially available calcium channel blockers are metabolized by CYP-IIIA IV, and so there's potential for a DDI where enzolutamide may decrease the plasma concentrations of these drugs.

00:17:45: If co-administration is necessary, the pharmacologic response of the calcium channel blocker should be monitored closely following the initiation or discontinuation of enzolutamide and its dosage adjusted as necessary.

00:17:57: So what are the alternative treatment options for managing hypertension for Bob?

00:18:02: One option to consider is using angiotensin-converting enzymes, or ACE inhibitors, like Benezapril, which has no known interactions with enzolutamide.

00:18:11: Another option could be beta blockers, such as Carvedolol, which also has a more favorable interaction profile with enzolutamide.

00:18:18: This

00:18:19: is very useful information.

00:18:20: Thank you, Dr.

00:18:21: Morgan, for sharing your expertise and insights.

00:18:24: My pleasure.

00:18:25: And one final thought.

00:18:27: As a medical oncologist for somebody like Bob, I'm always focused on managing and treating his prostate cancer.

00:18:33: Rather

00:18:33: than making changes on my own to a patient's blood pressure or cholesterol management plans, I work closely with a pharmacist and primary care and cardiology teams and defer to their clinical expertise in managing Bob's comorbidities.

00:18:45: By working together as a multi-disciplinary team, we can successfully optimize long-term outcomes for him.

00:18:51: That's really great, Dr.

00:18:52: Morgan.

00:18:53: Thanks again.

00:18:54: Now let's talk about managing a diabetes patient who is diagnosed with castrate-resistant prostate cancer and start by discussing the prevalence of diabetes among prostate cancer patients.

00:19:05: Dr.

00:19:05: Looney, could you shed some light on this?

00:19:08: Diabetes is highly prevalent among patients with prostate cancer, especially those over the age of sixty-five.

00:19:15: It's a significant concern that requires careful management alongside cancer treatment.

00:19:20: Type II diabetes mellitus is the predominant form of diabetes accounting for about ninety percent of cases.

00:19:28: Type II diabetes has been associated with an increased risk of developing several cancers, including liver, pancreatic, colorectal, renal, bladder, endometrial, and breast.

00:19:40: Interestingly, several meta-analysis have shown that type II diabetes is correlated with reduced risk of prostate cancer.

00:19:48: Despite this reduction, diabetes is associated with increased prostate cancer mortality.

00:19:53: Available reports and meta-analysis demonstrate that most anti-diabetic drugs do not increase the risk of prostate cancer incidents or disease progression.

00:20:03: In fact, some studies have shown a potential advantage of type II diabetes mellitus treatment in prostate cancer risk reduction and improvement in patient overall survival associated with Met boron therapy.

00:20:15: Can you discuss how you would treat a patient with prostate cancer and type II diabetes?

00:20:21: Here, we have Tim, a fifty-nine-year-old male, being treated with enzolutamide, or castration-resistant prostate cancer.

00:20:28: He's been diagnosed with type II diabetes for about four years and was prescribed glimeparide.

00:20:35: Glimeparide is metabolized in the liver by the cytochrome P-Four-Fifty system.

00:20:39: Enzolutamide is a known inducer of both CYP-II-C-IX and CYP-III-IV, which may contribute to relevant pharmacokinetic interactions between the two drugs.

00:20:50: What potential considerations should be taken into account when prescribing enzolutamide alongside glimeparide?

00:20:58: Sulfonylureas, including glimeparide, and a few others within this class of hypoglycemic agents are primarily metabolized by CYP-II-C-IX.

00:21:07: So there's the potential for a DDI resulting in reduced plasma concentration of glimeparide when given concurrently with enzolutamide.

00:21:15: Use of other anti-diabetic agents, such as DPP-IV inhibitors, may pose a similar risk since they are primarily metabolized by CIP-III, IV, and V. Because of the potential for these DDIs, we would strongly advise patients like Tim to work with their primary care physician or endocrinologist to carefully monitor their A-I-C status when taking enzolutamide, concomitant with glimeparide, as well as when enzolutamide is stopped.

00:21:43: Close monitoring is crucial to ensure that patients like Tim receive safe and effective treatment, and healthcare providers should closely monitor blood glucose levels and adjust medication doses as necessary to optimize diabetes management while minimizing the risk of adverse effects, especially when patients with prostate cancer are taking enzalutamide.

00:22:02: Are there alternative anti-diabetics for Tim that might help reduce the risk of DDIs with enzalutamide?

00:22:09: Yes, one possible alternative is Metformin, a widely prescribed medication for type II diabetes with no known interactions with enzalutamide.

00:22:17: SGLT-II inhibitors are also effective in treating type II diabetes.

00:22:22: Importantly, they are not metabolized by SIPs and have no known interactions with enzalutamide.

00:22:27: Assuming no contraindications or issues with tolerability, Metformin or SGLT-II inhibitors could be safely used with enzalutamide in Tim's case.

00:22:37: These are wonderful insights.

00:22:39: Thank you both, Dr.

00:22:40: Lunean and Dr.

00:22:40: Morgan's.

00:22:42: And we're almost up to the end of our podcast for today.

00:22:45: Before we wrap up, I'd like to ask both panel members to share their final thoughts or key takeaways on this important topic.

00:22:53: Thanks, Judith.

00:22:54: There are a few takeaways I'd like to leave with the listeners.

00:22:57: First and foremost, enzalutamide is a beneficial drug for the treatment of certain types of prostate cancer, but requires management of potentially significant drug interactions.

00:23:06: Most drug interactions stem from the fact that enzolutamide is a strong inducer of CYP-IIIA-IV, a hepatic cytochrome P-FOUR-FIFTY enzyme that is responsible for the metabolism of many other drugs on the market.

00:23:19: Based on the current understanding of enzolutamide drug interactions, nearly all of them can be effectively managed with appropriate knowledge of which drugs pose interaction risks, when dose adjustments are indicated, and when alternative drugs can be substituted.

00:23:31: I completely agree.

00:23:33: and I do have a few additional takeaways for the listeners.

00:23:37: Where DDIs post challenges with enzalutamide, it may be possible to alter dosing or prescribe alternative drugs, particularly with the integrated expertise of a multidisciplinary care team.

00:23:48: Prescribers should refer to prescribing information to assess the need for medication dose adjustments based on potential SIP or transporter effects.

00:23:57: However, it is crucial to recognize that prescribing information may not always capture all possible drug interactions.

00:24:03: especially with newer medications.

00:24:06: It's critical that we, as healthcare professionals, keep an open dialogue with our prostate cancer patients and be vigilant of potential polypharmacy throughout their treatment course.

00:24:16: And that's why collaboration among multidisciplinary teams of physicians, pharmacists, and other healthcare practitioners is vital.

00:24:24: By pooling our expertise and resources, we can optimize treatment decisions, mitigate risk, and improve patient outcomes.

00:24:30: Thank

00:24:32: you both.

00:24:33: We want our listeners to know that we collaborated with other investigators on a recent publication in Drug Safety, twenty-twenty-four, entitled Enzalutamide, Understanding and Managing Drug Drug Interactions to Improve Patient Safety and Drug Efficacy, which is a helpful resource with additional information on Enzalutamide and its related DDIs and a great supplement to this podcast.

00:24:56: That's all we have for today.

00:24:58: Have a great day, everyone.

00:24:59: Bye.

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