Assessing Trends in Cytokine–CYP Drug Interactions and Implications for Precision Medicine
Navigating the Evolving Landscape of Cytokine-Mediated CYP Interactions
Cytokines, the versatile signaling molecules of the immune system, have emerged as a critical factor in modulating the activity of drug-metabolizing enzymes and transporters. As the pharmaceutical industry continues to advance immunotherapies and innovative biologics, understanding the clinical impact of cytokine-mediated drug interactions has become paramount for ensuring optimal therapeutic outcomes and patient safety.
Cytokines: Regulators of the Immune Response
Cytokines are a diverse group of glycoproteins predominantly produced by T-cells, macrophages, and B-cells. These key mediators of inflammation can be triggered by pathogens, cancers, autoimmune conditions, or even certain drug therapies. Cytokines are classified into various subgroups, including tumor necrosis factors (TNFs), interleukins (ILs), lymphokines, interferons (IFNs), colony-stimulating factors (CSFs), and transforming growth factors. They can be either proinflammatory (e.g., IL-6, IL-12, IL-17, IL-23, TNF-α, IFN-γ) or anti-inflammatory (e.g., IL-1, IL-9, IL-10) in nature.
Cytokine-Mediated Regulation of Drug-Metabolizing Enzymes and Transporters
Cytokines have been shown to exert a significant impact on the expression and activity of drug-metabolizing enzymes, particularly the cytochrome P450 (CYP) family, as well as drug transporters. Proinflammatory cytokines, such as IL-6, TNF-α, and IFN-γ, have been found to downregulate the mRNA levels of CYP3A, CYP2C, and CYP2B6 in human hepatocytes. Conversely, the effect of cytokines on CYP2D6 has been less pronounced, with no significant changes reported in its mRNA or protein levels.
These cytokine-mediated alterations in drug-metabolizing enzymes and transporters can lead to changes in the systemic exposure of CYP-sensitive drug substrates, potentially impacting their efficacy and safety. For instance, the neutralization of cytokines by therapeutic proteins, such as anti-IL-6 and anti-IL-23 monoclonal antibodies, has been shown to result in changes in the systemic exposures of CYP3A, CYP2C19, and CYP1A2 substrates, ranging from approximately -58% to +35%.
Trends in Cytokine–CYP Drug Interactions
To assess the trends in cytokine-mediated CYP drug interactions, we queried the University of Washington Drug Interaction Database (UW DIDB) for sensitive substrates of CYP3A (simvastatin, midazolam), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), CYP2C9 (warfarin), and CYP1A2 (caffeine, tizanidine) when co-administered with a broad class of immunomodulators.
The analysis revealed the following key trends:
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CYP1A2 substrates: Minimal changes were observed, with the largest percent change in the area under the curve (AUC) of caffeine (approximately -35%) in the presence of the anti-IL-23 antibody risankizumab.
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CYP2C19 substrate: Co-administration of the anti-IL-6 antibody sirukumab resulted in up to a 48% decrease in the AUC of omeprazole.
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CYP3A substrates: Co-administration of anti-IL-6 (tocilizumab, sirukumab, sarilumab), anti-IL-17A (brodalumab), and anti-IL-23 (risankizumab) monoclonal antibodies led to significant changes in the AUC of CYP3A substrates, with the largest decrease observed for simvastatin (AUC decreased by 58%) when co-administered with tocilizumab.
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CYP2D6 and CYP2C9 substrates: No significant trends were observed for these CYP substrates in the presence of cytokine modulators.
Overall, the analysis suggests that while clinically meaningful changes in the systemic exposures of sensitive CYP substrates due to cytokine modulators appear to be of low incidence, potential interactions and implications for dose adjustments cannot be entirely ruled out, particularly in acute care settings.
Implications for Precision Medicine in Acute Care Settings
Recent case reports have highlighted the potential impact of cytokine-mediated CYP drug interactions in acute care settings. Mefford et al. (2022) reported that critically ill COVID-19 patients with acute respiratory distress syndrome required significantly higher doses of intravenous midazolam (a CYP3A substrate) to maintain sedation goals when co-administered with tocilizumab, an anti-IL-6 monoclonal antibody.
To assess the magnitude of this drug interaction, we performed simulations using a one-compartment pharmacokinetic model for intravenous midazolam. The simulations suggested a ~six- to seven-fold increase in the systemic clearance of midazolam to account for the observed ~six-fold dose adjustment required in these patients to achieve optimal sedation.
Similarly, Güneş et al. (2020) reported a potential drug interaction between warfarin (a CYP2C9 substrate) and tocilizumab, with no changes in coagulation parameters or bleeding risks. This interaction may be attributed to the restoration of CYP2C9 levels due to the neutralization of IL-6 by tocilizumab, leading to increased warfarin clearance.
These case reports highlight the importance of considering cytokine-mediated CYP drug interactions, particularly in acute care settings where patients may be at risk of developing a cytokine storm. Leveraging model-informed approaches to support precision dosing strategies may be required to optimize the dosing of sensitive CYP substrates in such critical care scenarios.
Assessing Cytokine–CYP Interactions During Drug Development
The increasing interest in the development of immunotherapies and cell therapies, such as bispecifics and chimeric antigen receptor T-cells, has further emphasized the need to understand cytokine-mediated drug interactions. These therapies have the potential to release cytokines during treatment, which may impact the pharmacokinetics and pharmacodynamics of concomitantly administered sensitive CYP substrates, especially in critical care settings.
Nonclinical and Clinical Assessments of Cytokine–CYP Interactions
During the early stages of drug development, in vitro assays in whole blood or peripheral blood mononuclear cells can provide a preliminary, qualitative assessment of cytokine release potential for an investigational agent. For cell therapies, the assessment of cytokine release is typically conducted in non-human primates prior to first-in-human studies, as these models closely mimic the human innate immune system.
The initial indication of cytokine release from nonclinical models can then be used to generate a preliminary assessment of cytokine-mediated CYP drug interactions using human hepatocyte models. However, these in vitro and nonclinical models are not designed to quantitatively predict clinical outcomes or advise on dose adjustments.
During first-in-human dose escalation studies of immunomodulators and cell therapies, the time of onset, magnitude, and duration of cytokine release should be carefully measured. This information can then be used to evaluate the potential impact on the pharmacokinetics of concomitantly administered sensitive CYP substrates, typically using a physiologically-based pharmacokinetic (PBPK) modeling approach.
Leveraging Model-Informed Approaches
Once an optimal dose or dose range of the therapeutic modality has been identified, the available data on the dose range/exposures and cytokine release profile can be used to evaluate the potential cytokine-mediated drug interactions with standard-of-care supportive therapies that may be sensitive CYP substrates. This PBPK-based approach can enable the prediction of cytokine-mediated drug interactions with CYP substrates/inhibitors/inducers typically administered in the intended patient population, especially during the later stages of drug development.
Additionally, population-based variability associated with cytokine release may be accounted for using a systems-based approach, as demonstrated for midazolam, where a population-based pharmacokinetic model has been developed using baseline C-reactive protein levels and organ failure as covariates on systemic clearance. Such an approach could aid in evaluating dose adjustments of CYP substrates and minimizing the impact on their efficacy and safety in acute care settings.
Conclusion: Navigating the Complexities of Cytokine–CYP Interactions
The analysis of trends in cytokine-mediated CYP drug interactions suggests that the overall incidences of clinically meaningful pharmacokinetic drug interactions are relatively low. While the magnitude of changes in the systemic exposures of CYP3A and CYP2C19 substrates can be substantial (up to ~60% decrease in AUC) in the presence of anti-IL-6 and anti-IL-23 monoclonal antibodies, the clinical relevance to overall safety and efficacy appears to be limited.
However, in clinical settings where high levels of IL-6 or IL-23 or high inter-individual variability in these cytokines may be prevalent, leveraging model-informed approaches to support a precision dosing strategy may be required for optimal dosing of sensitive CYP substrates, particularly in acute care settings.
As the pharmaceutical industry continues to advance immunotherapies and cell therapies, understanding the impact of cytokine-mediated CYP drug interactions will be crucial for ensuring the safe and effective use of these novel treatment modalities. By integrating nonclinical assessments, clinical data, and model-informed approaches, researchers and clinicians can navigate the evolving landscape of cytokine–CYP interactions and unlock the full potential of precision medicine.
