Introduction: Isoniazid (INH) plays an important role in prevention and treatment of tuberculosis (TB). However, large pharmacokinetic (PK) variations are observed in patients receiving standard INH dosages. Considering the influence of PK variations on INH efficacy or adverse reactions, we reviewed the population PK studies of INH and explored significant covariates that influence INH PK.
Methods: The PubMed and Embase databases were systematically searched from their inception to 30 January 2023. PPK studies on INH using a parametric nonlinear mixed-effect approach were included in this review. The characteristics and identified significant covariates of the included studies were summarized.
Results: Twenty-one studies conducted in adults, and seven in pediatrics were included. A two-compartment model with first-order absorption and elimination was the frequently used structural model for INH. NAT2 genotype, body size, and age were identified as significant covariates affecting INH PK variation. The median clearance (CL) value in the fast metabolizers was 2.55-fold higher than that in the slow metabolizers. Infants and children had higher CL per weight values than adults with the same metabolic phenotype. In pediatric patients, CL value increased with postnatal age.
Conclusions: Compared with slow metabolizers, the daily dose of INH should be increased by 200-600 mg in fast metabolizers. To achieve effective treatment, pediatric patients need a higher dose per kilogram than adults. Further PPK studies of anti-tuberculosis drugs are needed to comprehensively understand the covariates that affect their PK characteristics and to achieve accurate dose adjustments.
Keywords: Isoniazid; NAT2 genotype; individualization dose adjustment; nonlinear mixed-effect modeling; population pharmacokinetics.