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.

Figure 1

Predicted vs. observed concentration‐time profile for lopinavir/ritonavir (a), ritonavir (b), and predicted concentration‐time profile for midazolam (c) in patients with coronarivus disease 2019 (COVID‐19; blue) and people living with HIV (PLWH) a, b or healthy volunteers c (green). The red and dark red marker show clinically observed data in PLWH and patients with COVID‐19, (mean ± SD). The solid lines, the dashed lines, and the shaded area represents the mean of each simulation with a different IL‐6 concentration (1, 5, 10, 50, 100, 500, 1,000, 5,000, 10,000, and 50,000 pg/mL; Figure  S2 ), the mean, and the 95% confidence interval of all simulated scenarios to recover all possible IL‐6 concentrations in the simulations. Overlapping confidence intervals between predicted PLWH and COVID‐19 concentrations are displayed in the blue‐green shaded area. [Colour figure can be viewed at wileyonlinelibrary.com]