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\begin{document}

\title{Model-based precision dosing and remedial dosing recommendations for
delayed or missed doses of isoniazid in Chinese patients with
tuberculosis}



\author[1]{Jinmeng Li}%
\author[1]{Ruoyang Zhang}%
\author[1]{Gaoyi Yang}%
\author[2]{Qingshan Cai}%
\author[2]{Yazhen Lang}%
\author[2]{Fangming Zhong}%
\author[2]{Jinpeng Huang}%
\author[2]{Yuanyuan Chen}%
\author[2]{Yao Qin}%
\author[2]{Likui Fang}%
\author[2]{Bo Ye}%
\author[2]{Lihua Lin}%
\author[2]{Huihong Lin}%
\author[2]{Xinjun Cai}%
\author[1]{Kan Xu}%
\affil[1]{Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Aim: Isoniazid (INH) has been used as a first-line drug to treat
tuberculosis (TB) for more than 50 years. However, large
inter-individual variability was found in its pharmacokinetics, and how
to handle a delayed or missed dose of INH remains unclear. This study
aimed to develop a population pharmacokinetics (PPK) model of INH in
Chinese patients with TB to provide model-informed precision dosing and
explore appropriate remedial dosing regimens for non-adherent patients.
Methods: A nonlinear mixed-effects modeling was used to analyze the PPK
of INH. Using Monte Carlo simulations to determine optimal dosage
regimens and design remedial dosing regimens. A two-compartment model
well described the PPK of INH. Results: N-acetyltransferase 2 (NAT2)
genotype and body weight were identified as significant factors on INH
PK. Monte Carlo simulations determined optimal dosage regimens for
patients with different NAT2 genotype and body weight. For remedial
dosing regimens, the missed dose should be taken as soon as possible
when the delay does not exceed 12 h, and an additional dose is not
needed. On delaying a INH dose exceed 12 h, only need to take the next
single dose normally. Conclusion: PPK modeling and simulation provide
valid evidence on the precision dosing and remedial dosing regimen of
INH.%
\end{abstract}%



\sloppy


{[}09/04/2023{]}

Dear Editors,

I wish to submit an original article for publication in \emph{British
Journal of Clinical Pharmacology} titled ``Model-based precision dosing
and remedial dosing recommendations for delayed or missed doses of
isoniazid in Chinese patients with tuberculosis''.

This study aimed to develop a population pharmacokinetics (PPK) model of
isoniazid (INH) in Chinese patients with TB to provide model-based
precision dosing and explore appropriate remedial dosing regimens for
non-adherent patients. Although INH has been used as a first-line drug
to treat TB for decades years, large inter-individual variability was
found in its pharmacokinetics, leading to the clinical treatment failure
and drug resistance, and there is currently no uniform solution to this
problem. In addition, owing to current TB therapy duration requiring up
to 6 months, delayed or missed INH doses are common in clinical
practice. Nonadherence has also been reported as one of the most
important factors associated with the emergence of acquired drug
resistance. However, there are no studies on the remedies dosing
recommendations of INH for missed or delayed doing, the INH instructions
provided by the CFDA and FDA also do not mention remedies for missed or
delayed administration. Therefore, this study analyzed a total of 701
observations from 503 patients to establish a population pharmacokinetic
model of INH; N-acetyltransferase 2 (NAT2) genotype and body weight were
identified as significant factors on INH CL/F and Vc/F. Monte Carlo
simulations were used to determine optimal dosage regimens and design
remedial dosing regimens. Optimal dosage regimens were recomended for
patients with different NAT2 genotype and body weight. For remedial
dosing regimens, the missed dose should be taken as soon as possible
when the delay does not exceed 12 h, and an additional dose is not
needed at the next scheduled time. On delaying a INH dose exceed 12 h,
only need to take the next single dose normally. PPK modeling and
simulation provide valid evidence on the precision dosing and remedial
dosing regimen of INH.

This manuscript has not been published or presented elsewhere in part or
in entirety and is not under consideration by another journal. All study
participants provided informed consent, and the study design was
approved by the appropriate ethics review board. We have read and
understood your journal's policies, and we believe that neither the
manuscript nor the study violates any of these. There are no conflicts
of interest to declare.

Thank you for your consideration. We look forward to receiving comments
from the reviewers. If you have any queries, please don't hesitate to
contact me.

Sincerely,

Kan Xu

Affiliated Hangzhou Chest Hospital, Zhejiang University School of
Medicine.

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