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.
The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.
MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).
The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).
DISCUSSION
As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.
Paclitaxel
Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.22-27
The generic name is not the same as a generic drug, which may have slight differences from the brand name product.71 The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.72 During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.
Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.73-76
Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.
