Paclitaxel Drug-Drug Interactions in the Military Health System
Background: Paclitaxel is an antineoplastic agent used to treat breast, lung, endometrial, cervical, pancreatic, sarcoma, and thymoma cancer. However, drugs that induce, inhibit, or are substrates of cytochrome P450 (CYP) isoenzymes 2C8 or 3A4 may alter the metabolism of paclitaxel, potentially impacting its effectiveness. The purposes of this study are to provide an overview of paclitaxel use, identify potential drugs that interact with paclitaxel, and describe their clinical manifestations.
Methods: A retrospective analysis was performed on patients receiving paclitaxel to evaluate types and stages of cancer, treatment regimens, and adverse events of paclitaxel alone or paclitaxel in combination with other antineoplastic drugs, using data retrieved in March 2022 from the US Department of Defense Cancer Registry. Additionally, the study compared the health issues and prescriptions of patients who completed treatment with those who discontinued treatment. It evaluated interactions of paclitaxel with noncancer drugs, particularly antidepressants metabolizing and inhibiting CYP3A4, using data from the Comprehensive Ambulatory/Professional Encounter Record and the Pharmacy Data Transaction Service database. Data were retrieved in October 2022.
Results: Of 702 patients prescribed paclitaxel, 338 completed treatment. Paclitaxel discontinuation alone vs concomitantly (P < .001) and 1 drug vs combination (P < .001) both were statistically significant. Patients who took paclitaxel concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 9 to 56 prescription drugs, and those in the discontinued group were prescribed 6 to 70. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment.
Conclusions: The study provides a comprehensive overview of paclitaxel usage from 1996 through 2022 and highlights potential drug interactions that may affect treatment outcomes. While the impact of prescription drugs on paclitaxel discontinuation is uncertain, paclitaxel and antidepressants do not have significant drug-drug interactions.
METHODS
The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.
Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.
Data Extraction Design
The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.
Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).
Data Extraction Analysis
The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.
In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.70 Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.
