The authors thank Dr. Sellers for his commentary 1 on the drug–drug interaction (DDI) Tutorial 2. The authors agree, in general, that evaluation of pharmacokinetic DDIs does not explain all DDIs, but pharmacokinetic DDIs significantly improve dosing recommendations for new drugs (Table 1). The authors also agree that standard population studies do not always reflect the true risk or nature of DDIs in specific subgroups. Pharmacodynamic DDIs, which can be synergistic, additive, or antagonistic, are extremely important 3-5, typically specific for a therapeutic area (e.g., antiviral, pain, oncology) and can lead to unpredictable clinical outcomes. DDIs for biologics are due to the mechanism of action or modulation of disease pathophysiology 4. While pharmacodynamic and disease-specific interactions remain important, the approach to pharmacokinetic DDIs outlined in the Tutorial offers a robust scientific rationale, reflecting advances in our understanding of metabolizing enzymes and transporters. This information enables the development of sound dosing recommendations for DDIs across therapeutic areas (Table 1). Additionally, scientists should consider DDIs related to the underlying disease or therapeutic area. Dr. Sellers notes that patients are the true “victims” and doctors are the true “perpetrators” of DDIs; the authors agree that clinicians need additional training on the management of complex DDIs to decrease adverse events. The authors believe that the terms “victims” and “perpetrators” are clearly and informatively defined in the DDI tutorial. In cases of interaction between DRUG A (investigational drug) and DRUG B (concomitant medication), it is essential for clinicians to determine whether the dose adjustment is needed for DRUG A as the victim or for DRUG B as the victim when DRUG A acts as the perpetrator. Grouping these together obscures which drug is affected, whereas the “victim” and “perpetrator” terminology provides clarity. The DDI tutorial also gives recommendations about what information should be included in a label and how it should be provided. In addition, there should be collaboration among societies to explain complex DDIs to clinicians and trainees (focusing on audience) to improve prescribers' understanding of managing complex DDIs. Most importantly, the understanding of DDIs and the methods for detecting DDIs will improve by including the interplay between drug metabolizing enzymes and transporters using physiologically-based pharmacokinetic modeling, clinical studies in the patient population, real-world data that may be optimized through machine learning, and developing tools for individualized DDI risk assessment. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Sellers papers. To view this article, visit https://doi.org/10.1111/cts.70458.
Das et al. (Fri,) studied this question.