089: The Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic & Pulmonary Candidate Drug Concentrations

Statement of Purpose, Innovation or Hypothesis: Recent studies suggest that COVID-19 dysregulates CYP3A4 in a bidirectional tissue-specific manner, potentially causing intercompartmental differences in candidate drug concentrations and affecting therapeutic outcomes. The goal of this study is to investigate how the concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 affect intercompartmental candidate drug concentrations and therapeutic outcomes.

Description of Methods & Materials: Simcyp version 22.1 (Simcyp, Sheffield, UK) was used to perform physiologically based pharmacokinetic (PBPK) modeling of four CYP3A4 candidate drugs including nirmatrelvir/ritonavir, dexamethasone, clarithromycin, and itraconazole using published compound parameters and virtual trial information. The mechanistic multicompartment lung model in Simcyp was used without modifications. CYP3A4 abundance levels were concurrently decreased in the liver and increased in the lungs of virtual participants comprising healthy individuals and COVID-19 patients with varying disease severity including outpatient, non-ICU, and ICU hospitalized patients based on existing clinical data on CYP3A4 expression levels in these patient groups. We investigated the changes in systemic, pulmonary fluid, and tissue mass candidate drug concentrations across the four study cohorts. Finally, we evaluated the relationship between intercompartmental drug concentrations and the effective concentrations (EC) that determine therapeutic efficacy and safety using reported EC values of the candidate drugs for respiratory pathogens including SARS-CoV-2 (nirmatrelvir/ritonavir, dexamethasone, and itraconazole) and Streptococcus pneumoniae (clarithromycin).

Data & Results: The pulmonary concentrations of the investigated drugs continually increased across the different COVID-19 patient groups despite the upward increase in pulmonary CYP3A4 abundance with disease severity. The intercompartmental concentration ratios established in the healthy cohort were fairly maintained across the different COVID-19 cohorts. The ICU cohort had the highest percentage increase in PK parameters, with an AUC of 40%, 106%, 40%, and 136% for nirmatrelvir, dexamethasone, clarithromycin, and itraconazole, respectively relative to the healthy group (Figure 1). In the ICU cohort, nirmatrelvir maximum plasma concentration (C_max) exceeded the EC₉₀ of the omicron and delta variant by 135-fold and 46-fold, respectively (Table 1). Within the right lung lower lobe, nirmatrelvir C_maxfluid exceeded the EC₉₀ of the omicron and delta variant by 41-fold and 14-fold respectively, while the C_{maxtissuemass} was 76-fold higher than the EC₉₀ for the omicron variant and 26-fold higher than the EC₉₀ for the delta variant. Similarly, dexamethasone C_maxplasma, C_maxfluid, and C_{maxtissuemass} exceeded the IC₉₀ by 5-fold, 1-fold, and 2-fold respectively in the same ICU cohort. Unexpectedly, clarithromycin C_maxplasma, C_maxfluid, and C_{maxtissuemass} surpassed the minimum inhibitory concentration (MIC₉₀) of Streptococcus pneumoniae by 450-fold, 243-fold, and 1657-fold in the ICU cohort. Interestingly, Itraconazole C_maxplasma exceeded the EC₉₀ of the SARS-CoV-2 strain, hCoV-19/Germany/FI1103201/2020 by 4-fold in the ICU cohort. However, the EC₉₀ of the investigated SARS-CoV-2 strain exceeded the C_maxfluid by 16-fold while the C_{maxtissuemass} surpassed the EC₉₀ by 23-fold in the ICU cohort (Table 1).

Interpretation, Conclusion or Significance: Our PBPK modelling study demonstrates that hepatic CYP3A4 metabolism is the major driver of both systemic and pulmonary candidate drug concentrations. Insufficient itraconazole pulmonary fluid concentrations may underpin its limited efficacy for COVID-19 treatment while clarithromycin’s over-exposure warrants further safety investigation. Given that ICU patients had the most profound compartmental drug concentrations, dosing regimen optimization is required to improve therapeutic efficacy and safety.

Disclosures: Chukwunonso Nwabufo was a former employee of Gilead Sciences and was involved in the development of remdesivir and lenacapavir. Chukwunonso Nwabufo is employed by OneDrug Inc. The authors do not have any conflicting interests associated with this research.  This research is supported by grants from Canadian Institutes of Health Research, CIHR (Fund #514798 and # FRN 181381 awarded to Chukwunonso Nwabufo, and #511794 awarded to Chukwunonso Nwabufo and Theo Moraes).

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Additional Information/Authors: We appreciate Professor Amin Rostami-Hodjegan and Dr. Kayode Ogungbenro of the Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK for their support. Chukwunonso Nwabufo is a recipient of the Canadian Institutes of Health Research Doctoral Scholarship, Canadian Institutes of Health Research Doctoral Scholarship—Michael Smith Foreign Study Supplements Award, Ontario Graduate Scholarship, Pfizer Canada Graduate Fellowship, and Leslie Dan Faculty of Pharmacy Dean’s Fellowship.