Pharmacokinetic considerations to optimize clinical outcomes for COVID-19 drugs

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues

“…For example, CYP3A4 involved in the metabolism of dexamethasone, a corticosteroid drug often administered to hospitalized COVID-19 patients, is known to be dysregulated by inflammation ( Kumar and Trivedi, 2021 ; Dunvald et al, 2022 ). Also, nirmatrelvir, an antiviral drug used to treat SARS-CoV-2 infection is metabolized by CYP3A4 and is currently coadministered with ritonavir (an inhibitor of CYP3A4) to improve its bioavailability ( Nwabufo and Bendayan, 2022 ). Therefore, it is important to further investigate how SARS-CoV-2-associated inflammatory response will affect the PK profile of nirmatrelvir-ritonavir combination therapy for the treatment of COVID-19.…”

“…From the absolute quantitation, we observed significant differences in the expression of P-gp and MRP1 between the COVID-19 and control human lung tissues ( Figure 6B ). P-gp is involved in the transport of nirmatrelvir, remdesivir, and dexamethasone while MRP1 transports lopinavir and ritonavir ( Nwabufo and Bendayan, 2022 )—indicating a potential alteration in pulmonary drug PK/PD profile in COVID-19 patients. The lack of observable significant dysregulation in the protein expression of other DMETs in COVID-19 human lung tissues ( Figures 5 , 6 ) could be attributed to the potential variation in the stage of COVID-19 between cases, as well as comorbidities ( Table 1 ), ongoing medications, and genetic polymorphisms in the expression of DMETs for both COVID-19 and control cases.…”

“…This suggests a potential SARS-CoV-2-mediated increase in the expression of DMETs through the recruitment of inflammatory cells and may have implications for pulmonary drug PK/PD profiles. For example, CYP3A4 and ENT2 are involved in the disposition of remdesivir ( Nwabufo and Bendayan, 2022 ) and may be susceptible to an altered pulmonary PK/PD profile in the context of SARS-CoV-2 infection. Additionally, the observed COVID-19-related pulmonary pathologies could also reduce the expression of DMETs.…”

“…For example, DAD could alter the integrity of alveolar epithelial cells—which also house more than 90% of the investigated DMETs including CYP3A4 and P-gp. Our recent paper provides strategies for achieving optimal clinical efficacy and safety amidst SARS-CoV-2-associated inflammatory response ( Nwabufo and Bendayan, 2022 ) and should be considered in the clinical decision-making process for COVID-19 drugs.…”

“…At the molecular level, proinflammatory cytokines may dysregulate the expression of DMETs through xenosensing regulatory proteins including pregnane X receptor (PXR), constitutive androstane receptor (CAR), nuclear factor kappa B (NF-kβ), phosphorylated signal transducer and activator of transcription 3 (pSTAT3) that control transcription ( Wu and Lin, 2019 ; Stanke-Labesque et al, 2020 ; Dunvald et al, 2022 ). Also, inflammation-mediated damage of pulmonary cells housing DMETs, as well as recruitment of pulmonary immune cells such as macrophages (which also house DMETs) in response to SARS-CoV-2 infection could also alter local drug PK/PD profile ( Nwabufo and Bendayan, 2022 ). In general, all these effects associated with an immune response to SARS-CoV-2 infection could lead to distinct PK/PD profiles in peripheral tissues and systemic circulation with potential clinical drug safety and efficacy issues for COVID-19 patients, especially those with polypharmacy.…”