Pharmacokinetic Drug-Drug Interaction Potential of Oral Anticancer Drugs

Drug-drug interaction (DDI) management is critical for safe and effective use of oral anticancer drugs (OADs). Our study objectives were to (i) compile clinically relevant pharmacokinetic (PK) DDI mechanisms for OADs and (ii) assess the prevalence of PK potential DDIs (PDDIs) in patients with advanced solid cancers. OADs approved through January 2023 were assigned DDI mechanisms based on studies obtained from drug labels and primary literature showing ≥ 2-fold exposure change or significant adverse health outcomes during co-administration with interacting drugs. Electronic health records of 3,697 solid cancer patients were reviewed retrospectively to detect PDDIs, defined as overlapping prescriptions of OADs with relevant interacting drugs. FDA labels were reviewed for 99 OADs, and 239 studies were extracted from the primary literature, yielding a total of 748 drug-drug pairs for analysis. Eighty-five OADs (85.9%) had ≥ 1 DDI mechanism. The most common DDI mechanisms were victims with metabolic inducers (71.7%), CYP3A substrates (55.6%), CYP3A perpetrators (29.3%), and victims with acid reducers (17.2%). Our primary literature search detected clinically relevant DDI mechanisms without actionable recommendations in the drug labels for 14 drugs. Among patients prescribed ≥ 1 OADs (46.9%), 17.4% had ≥ 1 PDDI, most commonly involving OADs acting as CYP3A (58.9%) or CYP2D6 (32.5%) perpetrators. Most OADs (~86%) had ≥ 1 DDI mechanism, and ~17% of solid tumor board patients had a clinically relevant PDDI.