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\begin{document}

\title{Ineffective of lopinavir/ritonavir and chloroquine for a COVID-19
treatment: A perspective of physiologically-based pharmacokinetic and
pharmacodynamic modelling}



\author[1]{Teerachat Saeheng}%
\author[1]{Juntra Karbwang}%
\author[2]{Kesara Na-Bangchang}%
\affil[1]{Thammasat University}%
\affil[2]{Thammasat University (Rangsit Campus)}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\begin{abstract}
Ineffective selection of therapeutic drugs during an urgent situation
leads to failure for COVID-19 treatment in large clinical trials,
resulting in wasting time and cost. We aimed to demonstrate the utility
of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD)
modeling to support the withdrawal of chloroquine and ritonavir-boosted
lopinavir (LPV/r) for COVID-19 treatment. The developed whole-body PBPK
models were validated against clinical data. Model validation was
performed using acceptable methods. The inhibitory effect was calculated
to demonstrate drug efficacy. Various regimens of chloroquine and LPV/r
for COVID-19 treatment in different clinical trials were used for a
simulation. The risk of cardiotoxicity following high dose chloroquine
administration was assessed. The effect of lung pH on drug
concentrations in epithelial lining fluid (ELF) following a high dose of
chloroquine and LPV/r was evaluated. The whole-body PBPK models were
successfully developed (AAFEs of 1.2-fold). The inhibitory effect (\%E)
of chloroquine following high dose regimens in both ELF and bronchial
epithelial cells (BEC) were lower than 2 and 1\%, respectively. The
corresponding values for the high dose of LPV/r were 40 and 2\%,
respectively. The risk of prolonged QTc in the population was higher
than 20\%. In addition, the \%E of chloroquine was increased to 76\% at
pH 5.6 and decreased to 0.13\% at pH 7.5. The change in pH in ELF had no
influence on LPV/r concentrations. PBPK/PD modelling supports the
withdrawal of chloroquine and LPV/r for COVID-19 treatment as an
effective tool for the selection of therapeutic drug regimens in urgent
situation.%
\end{abstract}%



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