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Physiologically Based Pharmacokinetic Modelling to Investigate the Impact of the Cytokine Storm on CYP3A Drug Pharmacokinetics in COVID-19 Patients.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2022 Mar; Vol. 111 (3), pp. 579-584. Date of Electronic Publication: 2021 Sep 22. - Publication Year :
- 2022
-
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.<br /> (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Adult
COVID-19 metabolism
Cytochrome P-450 CYP3A pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors pharmacokinetics
Cytokine Release Syndrome drug therapy
Cytokine Release Syndrome metabolism
Cytokines metabolism
Humans
Metabolic Clearance Rate drug effects
Middle Aged
Models, Biological
COVID-19 Drug Treatment
COVID-19 complications
Cytochrome P-450 CYP3A metabolism
Cytokine Release Syndrome virology
Lopinavir pharmacokinetics
Midazolam pharmacokinetics
Ritonavir pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 111
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 34496043
- Full Text :
- https://doi.org/10.1002/cpt.2402