Sheng Yuan Chin1, Dr Kenneth Hor Cheng Koh1, Dr James Chun Yip Chan1,2
1Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), 2A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR)
Introduction: Caffeine, a psychostimulant consumed by 80% of world population every day, is predominantly metabolized by cytochrome P450 enzyme, CYP1A2 in liver. Hence, caffeine is widely used as a probe for metabolic phenotyping of CYP1A2. Elevated cytokines such as interleukin-6 (IL-6), IL-1ß and tumor necrosis factor-alpha (TNF-a) have been shown to suppress CYP1A2 activity in in vitro experiments.[1,2] There were also studies investigating the in vivo influence of induced/suppressed IL-6 levels on CYP1A2 activity using physiologically-based pharmacokinetic (PBPK) model, albeit the influence is not conclusive.[3–6] Grzegorzewski et al. suggested that the main drug-disease interaction for caffeine is liver dysfunction.[7] However, there is no direct study on the caffeine clearance (CL) differences in healthy adults and cancer subjects without liver dysfunction. This study investigates the drug-disease interaction of caffeine in cancer subjects by accessing the impact of cytokine-mediated suppression of CYP1A2 activity and caffeine CL with PBPK modelling approach, guided by the observations showing the elevated levels for IL-6, IL-1ß and TNF-a in some cancer populations.[8–10] Methods: A PBPK model of caffeine was constructed for the healthy adult population in SimBiology (MathWorks, R2024a) using published human in vitro absorption, distribution, metabolism and excretion (ADME) data and verified using clinical PK data. The model was extrapolated to the cancer population by modifying the human physiology data such as age, weight, organ volumes, blood flow rates, albumin binding and others to predict the PK of caffeine in cancer subjects. The suppressions of CYP1A2 activity by IL-6, IL-1ß and TNF-a were derived with the four-parameter logistic (4PL) regression equation using in vitro inhibition data such as EC50 (cytokine concentration resulting in half maximal suppression), Emin and cytokines level in cancer subjects. EC50 of CYP1A2 suppression for IL-6, IL-1ß and TNF-a are 909.02, 13.85 and 837.2 pg/mL respectively.[1,2] Results: When comparing the reported PK data of caffeine (3 healthy[11–13] and 4 cancer[14–17] studies), we observed that the AUC increased by 70% and CL reduced by 38% in cancer subjects as compared to healthy adults, necessitating the study of possible reasons behind the reduced CL. First, we verified our caffeine PBPK model for the healthy population against the observed healthy PK data (fold differences of 0.7, 0.78 and 1.28 for Cmax, AUC and CL respectively). The fold-difference was calculated as the quotient of predicted and observed values. Next, the model was extrapolated to the cancer population and a suppression factor for CYP1A2 metabolic activity was incorporated to reflect the cytokine-induced suppression. The observed IL-6 and IL-1ß levels in cancer subjects were 14.3 pg/mL[18] and 5.2-19.8 pg/mL[19,20] respectively. By using the 4PL equation, the suppression factor of IL-6 in cancer subjects is 0.98 (equivalent to only 2% suppression in CYP1A2 activity). Most of the predicted PK parameters underperform the observed cancer PK data except Cmax (fold differences of 1.05, 0.54 and 1.86 for Cmax, AUC and CL respectively), indicating that the CYP1A2 suppression induced by IL-6 is insufficient to account for the reduction in caffeine CL in cancer subjects. On the other hand, the range of the suppression factor for IL-1ß is 0.42-0.73 (equivalent to 27-58% suppression in CYP1A2 activity). The predicted PK parameters at suppression factor of 0.42 are comparable with clinical data (fold differences of 1.12, 1.23 and 0.81 for Cmax, AUC and CL respectively), suggesting that the observed CYP1A2 suppression can be explained by the highest observed IL-1ß level (19.8 pg/mL). The suppression effect of TNF-a on caffeine CL is presumably minimal because of the high EC50 on CYP1A2 suppression (similar to that of IL-6). We did not explore the interplay of suppression effect among these cytokines, which may not be purely additive. For example, there was a study showing the cross-regulation between IL-6 and TNF-a in rheumatoid arthritis patients.[21] Sensitivity analyses established that minimal change in PK profile of caffeine was observed as a result of the changes in unbound fraction in plasma (lower plasma albumin level), blood-to-plasma ratio (lower hematocrit) and blood flow rates reported in cancer subjects. Conclusion: In this study, we investigated the drug-disease interaction for caffeine in cancer subjects and our PBPK model demonstrates that IL-1ß has the most significant influence on the suppression of CYP1A2 activity among the studied cytokines (IL-6, IL-1ß and TNF-a). This has implications on the exposure of xenobiotics that are primarily metabolized by CYP1A2 in cancer subjects.
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Reference: PAGE 33 (2025) Abstr 11373 [www.page-meeting.org/?abstract=11373]
Poster: Drug/Disease Modelling - Oncology