Commentary on: Pharmacist-driven interventions to de-escalate urinary antimuscarinics in the Program of All-Inclusive Care for the Elderly.

Abstract

We would like to thank Drs Bankes and Turgeon for their recent reply to our commentary on their article “Pharmacist-driven interventions to de-escalate urinary antimuscarinics in the Programs of All-Inclusive Care for the Elderly.”1 We sincerely appreciate their perspective on the need to consider minimizing the potential for drug–drug interactions (DDIs) in older adults with overactive bladder (OAB) who experience polypharmacy. As mentioned in their response, vibegron, a β3-adrenergic receptor agonist approved to treat OAB, does not inhibit the cytochrome P450 2D6 isoenzyme (CYP2D6),2 potentially reducing the risk of patients experiencing DDIs when it is coadministered with CYP2D6 substrates. We would like to briefly expand on the available evidence concerning coadministration and codispensing of β3-adrenergic receptor agonists and CYP2D6 substrates. When CYP2D6 substrates and inhibitors are coad-ministered, patients may experience elevated exposure to the substrate, potentially leading to an increased risk of adverse events.3, 4 In addition to in vitro data demonstrating that vibegron does not inhibit CYP2D6,5 two phase 1 clinical trials found that coadministration of vibegron did not substantially alter the geometric mean maximum plasma concentration (Cmax) and area under the curve (AUC) of the CYP2D6 substrates tolterodine and metoprolol.6 In contrast, two clinical DDI studies found that coadministration of mirabegron increased the Cmax and AUC of the CYP2D6 substrates tolterodine, metoprolol, and desipramine.7, 8 These data suggest that coadministration of a CYP2D6 substrate with mirabegron may increase CYP2D6 substrate exposure, potentially increasing the risk of DDIs and associated adverse outcomes, and the mirabegron package insert therefore advises prescribing clinicians to provide appropriate monitoring and consider making dose adjustments when mirabegron is used concomitantly with a CYP2D6 substrate. Coadministration with vibegron is unlikely to impact CYP2D6 substrate metabolism because vibegron is eliminated via the CYP3A4 metabolic pathway. However, as noted by Drs Bankes and Turgeon, vibegron administration can increase serum digoxin concentrations,2 which may make vibegron inappropriate for some patients. Data suggest that codispensing of mirabegron and CYP2D6 substrates may be common. A retrospective analysis of 106,260 commercially insured adult patients who were dispensed mirabegron between January 2011 and December 2019 found that 68.5% had overlapping dispensing with ≥1 CYP2D6 substrates.9 Among patients ≥65 years of age, 72.1% had CYP2D6 substrate dispensations that overlapped with mirabegron.9 A separate retrospective analysis of pharmacy claims from 159,785 residents in long-term care facilities who were dispensed OAB medications between May 1, 2013, and May 1, 2018, found that 93% of residents who received mirabegron were dispensed a CYP2D6 substrate during the analysis period.10 Owing to study limitations, it is unknown if the CYP2D6 substrate dispensing overlapped with mirabegron dispensing, if residents took both the CYP2D6 substrate and mirabegron concurrently, or if prescribing clinicians made proactive dose adjustments to account for coadministration.10 These results suggest that, despite warnings in the prescribing information and potential DDI warnings in electronic medical records, prescribing of mirabegron with CYP2D6 substrates is a common occurrence, although this may be due to necessity, for example, to avoid the use of anticholinergics in older adults or to treat serious conditions such as depression or cardiovascular disease. Additional analyses are needed to determine whether codispensing of mirabegron and CYP2D6 substrates leads to an increased risk of adverse outcomes. In their response to our previous commentary, Drs Bankes and Turgeon described the process used in the PACE program to quantify patient's risk of DDIs, considering anticholinergic burden and CYP450 interaction burden, which often resulted in a recommendation to discontinue anticholinergic therapy for OAB rather than switch to mirabegron. They emphasized the need for OAB treatment decisions to be individualized for each patient and appropriately noted that nonpharmacologic treatment may be the best option for some patients, in accordance with OAB clinical practice guidelines from the American Urological Association and the Society of Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction.11 We concur and hope that the practices described in the PACE program may serve as a model for continued improvement in monitoring patient medication lists for potential DDIs, recommending discontinuation of potentially inappropriate medications, and switching to other effective OAB medications when appropriate. The first draft of this Letter to the Editor was written by a medical writer under the direction of Daniel Snyder and Salim Mujais. Daniel Snyder and Salim Mujais critically reviewed the letter and approved the final version. Medical writing and editorial support were provided by Joseph Kruempel, PhD, of The Curry Rockefeller Group, LLC (Tarrytown, NY), and were funded by Urovant Sciences (Irvine, CA). This work was supported by Urovant Sciences. Daniel Snyder and Salim Mujais are employees of Urovant Sciences. Urovant Sciences funded medical writing and editorial support for the preparation of this letter.