Safety and Dosage Considerations for PARP Inhibitors

Video

Dr Haumschild explores considerations for safe and appropriate dosing for patients receiving PARP inhibitor therapy.

Ryan Haumschild, PharmD, MS, MBA: There are some drug interactions and drug-food interactions that we want to think about when we’re looking at PARP inhibitors and their management. Let’s start with olaparib, a well-known PARP inhibitor used across a ton of patient types. But we also know that it is metabolized by cytochrome P450 and has CYP3A, and it induces CYP3A and CYP2B6. You want to avoid those potent inhibitors. Those are the types of things when thinking about antibiotics like azithromycin and erythromycin. Even rifampin would be another 1 that you want to think about, in addition to antifungals and other medications that come into play.

When I think about rucaparib, it’s metabolized by the cytochrome 2D6 and, to a lesser extent, cytochrome 1A2 and 3A4. You want to be cautious with some of those potent CYP3A4/5 inducers or inhibitors. Those substrates would be things like different cyclosporines, fentanyl, and some of those other treatments like sirolimus and tacrolimus that could impact the uptake in the ultimate use of those medications. Lastly, you have niraparib. That’s metabolized, but there are no significant interactions with the cytochrome pathway. Therefore, it might have fewer drug-drug interactions than when we think about some of the other PARP inhibitors.

[For the dosing schedule for PARP inhibitors] let’s take olaparib, for example. We start with a starting dosage of 300 mg twice daily, but then we want to think about dosage reductions. So we can go to 250 mg twice daily, and then a further reduction can take it to 200 mg twice daily. Those reductions play an important role especially as patients have more treatment-related toxicities because our goal is to keep them on therapy longer. Let’s talk about rucaparib. You start with 600 mg twice a day as the starting dosage, but you can reduce the first time to 500 mg twice a day. You can go to a second reduction to 400 mg twice a day. Depending on whether it’s grade 3 or 4 or the adverse effects, you can do a third reduction to 300 mg twice a day. What I like about that dosing scheme is you give the opportunity for that patient to have several dosage reductions. As they proceed in their therapy, you can ultimately modify the dose to keep them on therapy longer and reduce the impact of those adverse effects throughout treatment.

Let’s talk about niraparib. The starting dosage for that medication is 300 mg once daily, but with the first reduction it goes down to 200 mg once daily. We can even do a second dosage reduction to 100 mg once daily. If you have to go below that, we look at discontinuation, but at least we have options when we’re looking at the patient’s total care journey. We also have to educate them. Dosage reduction might be part of your journey. It’s not necessarily a bad thing, and we’re going to be proactive when we do that so you can stay on therapy longer.

PARP inhibitors are such a great medication. The fact that they can take it orally and at home, and have dose reductions, is a great option to have. You want to have that on your tool belt when you’re treating patients. But there are adverse events that come into play. There are some common adverse events I think about when I’m looking at a patient on a PARP inhibitor. No. 1 is fatigue. We’ve seen this in the clinical trial. You’ll also see anemia, neutropenia, and thrombocytopenia to a further extent. You also can see nausea and vomiting and some decreased appetite. Some of these adverse effects had a higher incidence compared with the placebo arms, so that’s initially what we’re going to educate patients on. If you start to feel fatigued, it might be part of your normal treatment journey, but let us know. We’ve got to make sure we’re supplying you the supportive care medications and exercising the dosage reductions when appropriate and when needed. Lastly, we want to make sure it’s not rate limiting, so you have to abandon therapy before we can do something about it.

Transcript edited for clarity.

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