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. 2023 Dec;31(2):95-105.
doi: 10.1007/s40199-023-00463-1. Epub 2023 May 24.

Simulation of drug-drug interactions between breast cancer chemotherapeutic agents and antiemetic drugs

Subrata Deb  1 , Robert Hopefl  2
Affiliations

Simulation of drug-drug interactions between breast cancer chemotherapeutic agents and antiemetic drugs

Subrata Deb et al. Daru. 2023 Dec.

Abstract

Background: Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either inhibitors or inducers of cytochrome P450 (CYP) enzymes, while anticancer drugs are metabolized by CYPs.

Objectives: The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents.

Methods: The Drug-Drug Interaction™ module of GastroPlus™ was employed to assess CYP-related interactions between antiemetic and anticancer therapy combinations. The CYP inhibitory or inducing parameters (IC50, Ki, EC50) used in simulations were obtained from the literature.

Results: Analyses of twenty-three BCa drugs indicated that 22% of the chemotherapeutic drugs do not need an antiemetic agent due to their low emetogenicity, whereas 30% of the anticancer drugs are not metabolized by CYPs. The remaining eleven anticancer drugs metabolized by CYPs generated ninety-nine combinations with nine antiemetics. Simulation of DDIs suggest that about half of the pairs did not demonstrate any potential for DDI, whereas 30%, 10%, and 9% of the pairs showed weak, moderate, and strong interaction potential, respectively. In the present study, netupitant was the only antiemetic that showed strong inhibitory interactions (predicted AUC ratio > 5) with CYP3A4-metabolzied anticancer therapies (e.g., docetaxel, ribociclib, olaparib). Moderate to no interactions were observed with ondansetron, aprepitant, rolapitant, and dexamethasone in combination with anticancer agents.

Conclusion: It is critical to recognize that these interactions can get amplified in cancer patients because of the severity of the disease and chemotherapy toxicities. Clinicians need to be aware of the DDI likelihood of the drug combinations used in BCa treatment.

Keywords: Antiemetics; Chemotherapeutic agents; Cytochrome P450; Drug-drug interaction; Simulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart describing how the breast cancer treatment protocols and literature were analyzed to identify the chemotherapeutic drugs and antiemetics used in combination. CYP substrate profile of the chemotherapeutic agents and CYP modulating profile (IC50/Ki/EC50 values) of antiemetic agents were screened
Fig. 2
Fig. 2
CYP-related drug-drug interaction susceptibility profile of breast cancer chemotherapeutic drugs. The ability of chemotherapeutic agents to cause emesis was considered
Fig. 3
Fig. 3
Simulated drug-drug interaction outcomes between breast cancer chemotherapeutic and antiemetic agents. N/A, classifications resulted from GastroPlus™ when there were no common CYP enzymes between the victim drug and perpetrator
See this image and copyright information in PMC

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