Implementing a drug interaction protocol for oral systemic anti-cancer therapy with focus on CDK4/6 inhibitors.
Authors: Flynn Calvin R. , McMahon Eileen , Iqbal Shahid , McLoughlin Karen , Meaghar Ashleigh , Copty Nadine , Cristea Andra Florentina , Farooq Fahad , Khalid Tebyan , Murphy Catherine , Ronan Karine , Ryan Niamh , Yong Nicole , Harrold Emily 
Published: September 2024

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Background:
Oral anti-cancer therapies (OACTs) are being increasingly used. Despite their convenience, OACTs introduce challenges with adherence, prescribing errors, and high incidence of drug-drug interactions (DDIs). Currently, there are limited guidelines for DDI checking. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the management of metastatic ER+/HER2- breast cancer. While an overall survival benefit has been demonstrated with Ribociclib, its use can be problematic due to frequent DDIs and the risk of QTc prolongation. DDIs are routinely checked in our center with two interaction checkers, but they are not always documented due to a lack of a standardized protocol. This study aims to evaluate current DDI checking practices, identify common DDIs, and implement a systematic DDI protocol.
Methods:
A retrospective review was conducted on patients (pts) prescribed CDK4/6i in our center from Jan 2023 to Apr 2024. Data on pt demographics, treatment, DDI documentation, toxicity, and survival were collected. Retrospective DDI checks using Lexi-Interact and Drugs.com were performed.
Results:
A total of 65 pts were included, with 38 on Ribociclib and 27 on Palbociclib. The median follow-up was 11.6 months (range: 1-71). The median age of pts on Ribociclib was 54 (range: 35-77), compared to 61 (range: 44-82) on Palbociclib. The median number of medications was three with Ribociclib and five with Palbociclib. Seven pts (26%) were prescribed Palbociclib due to contraindications to Ribociclib, including cardiac disease (n=2), QTc-prolonging medications (n=4), and advanced age (n=1). DDI checks were documented in 46% of Ribociclib and 14% of Palbociclib pts (p=0.0063). There was a weak negative correlation between DDI documentation and toxicity, stronger in the Palbociclib arm (-0.079 for Ribociclib vs. -0.335 for Palbociclib). Retrospective checks revealed DDIs in 50% of Ribociclib and 52% of Palbociclib pts. Major DDIs were identified in 21% of Ribociclib and 7% of Palbociclib pts (p=0.133). Common major DDIs involved opioids and QTc-prolonging medications, most frequently antidepressants. Grade ≥3 toxicity occurred in 49% of Ribociclib vs. 64% of Palbociclib pts (p=0.21). Ribociclib caused more rash, liver toxicity, and diarrhea, while Palbociclib had significantly more grade ≥3 neutropenia (48% vs. 21%, p=0.042). No QTc prolongation was observed. Dose reductions were more common with Palbociclib (48% vs. 32%, p=0.27). There was no significant difference in survival data.
Conclusions:
Our findings highlight the importance of systematic DDI checks in pts receiving OACTs. Implementing a standardized protocol could reduce adverse interactions and improve pt outcomes. Further studies are needed to validate these findings and develop DDI guidelines. A standardized DDI protocol has now been developed for our center, with plans to re-audit after implementation.