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