Physiologically Based Pharmacokinetic Modelling to Investigate the Impact of the Cytokine Storm on CYP3A Drug Pharmacokinetics in COVID‐19 Patients

Abstract

Patients with coronavirus disease 2019 (COVID‐19) may experience a cytokine storm with elevated interleukin‐6 (IL‐6) levels in response to severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). IL‐6 suppresses hepatic enzymes, including CYP3A; however, the effect on drug exposure and drug‐drug interaction magnitudes of the cytokine storm and resulting elevated IL‐6 levels have not been characterized in patients with COVID‐19. We used physiologically‐based pharmacokinetic (PBPK) modeling to simulate the effect of inflammation on the pharmacokinetics of CYP3A metabolized drugs. A PBPK model was developed for lopinavir boosted with ritonavir (LPV/r), using clinically observed data from people living with HIV (PLWH). The inhibition of CYPs by IL‐6 was implemented by a semimechanistic suppression model and verified against clinical data from patients with COVID‐19, treated with LPV/r. Subsequently, the verified model was used to simulate the effect of various clinically observed IL‐6 levels on the exposure of LPV/r and midazolam, a CYP3A model drug. Clinically observed LPV/r concentrations in PLWH and patients with COVID‐19 were predicted within the 95% confidence interval of the simulation results, demonstrating its predictive capability. Simulations indicated a twofold higher LPV exposure in patients with COVID‐19 compared with PLWH, whereas ritonavir exposure was predicted to be comparable. Varying IL‐6 levels under COVID‐19 had only a marginal effect on LPV/r pharmacokinetics according to our model. Simulations showed that a cytokine storm increased the exposure of the CYP3A paradigm substrate midazolam by 40%. Our simulations suggest that CYP3A metabolism is altered in patients with COVID‐19 having increased cytokine release. Caution is required when prescribing narrow therapeutic index drugs particularly in the presence of strong CYP3A inhibitors.

Physiologically Based Pharmacokinetic Modeling To Predict Drug-Biologic Interactions with Cytokine Modulators: Are These Relevant and Is Interleukin-6 Enough?

“…Data for the in vitro suppression of CYP activity or mRNA from Dickmann et al (2011) have been used to successfully describe the clinical consequences of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 suppression by IL-6 in PBPK models (Machavaram et al, 2013(Machavaram et al, , 2019Jiang et al, 2016;Xu et al,. 2015;Stader et al, 2021;Lenoir et al, 2021c). The former three models are designed to capture the therapeutic protein-drug interactions in patients who have chronically raised IL-6 levels (Machavaram et al, 2013(Machavaram et al, , 2019Jiang et al, 2016).…”

“…In contrast, the models published in Xu et al (2015), Stader et al (2021) and Lenoir et al (2021) focus on transiently raised IL-6 levels. IL-6 levels increased rapidly to a mean peak of ~ 1600 pg/mL (60,000 pg/mL in the subject with the highest levels) at 6 h post blinatumomab administration and then decreased to baseline by 48 h (Xu et al, 2015).…”

“…Physiologically-based pharmacokinetic (PBPK) modeling has been used successfully to predict the impact of raised IL-6 on CYP activities (Machavaram et al, 2013(Machavaram et al, , 2019Jiang et al, 2016;Xu et al,. 2015;Stader et al, 2021;Lenoir et al, 2021). Beyond IL-6, evidence to support a direct effect of other cytokines on CYP activity remains inconclusive.…”

Therapeutic targets and functions of curcumol against COVID-19 and colon adenocarcinoma

“…The other target of curcumol, CYP3A4, is a member of the cytochrome P450 superfamily of enzymes. Many clinical trials suggested the importance of the cytochrome P450 system in the drug discovery of COVID-19 (40)(41)(42) because CYP3A metabolism is altered in patients with COVID-19 having increased cytokine release. In addition, an in vitro study of colon cancer stem cells demonstrated the contribution of CYP3A4 in the chemoresistance of colon cancer and its negative impact on disease-free survival in the patients (43).…”

Not your usual drug‐drug interactions: Monoclonal antibody–based therapeutics may interact with antiseizure medications

“…Recently, COVID-19 infection was associated with higher concentrations of lopinavir (a CYP3A4 substrate) than in patients with HIV 37,38 (Figure 2), and the related cytokine storm was predicted to increase the exposure to midazolam. 39 In that study, as in the other studies described below, midazolam was used as a prototypical CYP3A4 substrate and not as an anticonvulsant. Together, the findings from these works imply that systemic inflammation may be associated with phenoconversion of SMD metabolism toward generally poorer metabolizing phenotypes.…”