<div>[09/04/2023]</div><div>Dear Editors,</div><div>I wish to submit an original article for publication in <i>British
Journal of Clinical Pharmacology</i> titled “Model-based precision dosing
and remedial dosing recommendations for delayed or missed doses of
isoniazid in Chinese patients with tuberculosis”.</div><div>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.</div><div>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.</div><div>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.</div><div>Sincerely,</div><div>Kan Xu</div><div>Affiliated Hangzhou Chest Hospital, Zhejiang University School of
Medicine.</div>