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Physiologically‐Based Pharmacokinetic Modelling to Investigate Baricitinib and Tofacitinib Dosing Recommendations for COVID‐19 in Geriatrics
Author(s) -
Wang Ziteng,
Chan Eric Chun Yong
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2600
Subject(s) - medicine , tofacitinib , dosing , geriatrics , physiologically based pharmacokinetic modelling , population , pharmacokinetics , pharmacology , intensive care medicine , rheumatoid arthritis , environmental health , psychiatry
Janus kinase (JAK) inhibitors baricitinib and tofacitinib are recommended by the US National Institutes of Health as immunomodulatory drugs for coronavirus disease 2019 (COVID‐19) treatment. In addition, baricitinib has recently received Emergency Use Authorization from the US Food and Drug Administration, although the instruction provided dosing information only for adults. Geriatrics with organ dysfunction are one of the most vulnerable cohorts when combating the pandemic. The aim of the present work was to evaluate current dosing strategies of baricitinib and tofacitinib for potential COVID‐19 treatment for White and Chinese geriatric patients with chronic renal impairment. An established physiologically‐based pharmacokinetic (PBPK) modeling framework for age‐dependent simulations was utilized. PBPK drug models adopted from literature were first verified. Several population models representing different age groups, ethnicities, and stages of renal impairment were used for prospective simulations. Notwithstanding the increase in systemic exposure of both drugs resulting from renal dysfunction was more pronounced for geriatrics than general White populations, our simulations confirmed their current dosage adjustments based on renal functions are broadly adequate. The exception being White older subjects with mild renal impairment where current recommendation of 4 mg baricitinib yielded a 2.31‐fold increase in systemic exposure, and reduction to 2 mg could mitigate the potential risk to an acceptable 1.15‐fold. Comparable relationships between systemic exposure and renal dysfunction were observed for both drugs in the Chinese population. In summary, PBPK modeling of both JAK inhibitors supports the rational and prudent dose adjustments of these COVID‐19 therapeutics among adult patients of different age groups and renal functions.