Parametric population pharmacokinetics of isoniazid: a systematic review

ABSTRACT

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
• individualization dose adjustment
• population pharmacokinetics
• nonlinear mixed-effect modeling
• NAT2 genotype

Article highlights

• A two-compartment model with first-order absorption and elimination is the most frequently used structural model to describe the pharmacokinetics of INH.

• The pharmacokinetics of isoniazid was significantly affected by NAT2 genotype, body size, and age.

• The median clearance of isoniazid in fast metabolizers was 2.55-fold higher than that in slow metabolizers.

• Compared with slow metabolizers, the daily dose of isoniazid should be increased by 200-600 mg in fast metabolizers.

• Pediatric patients show a higher clearance per kilogram than adult patients, which leads to a higher dose per kilogram to maintain the target concentration.

• 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.

Acknowledgments

The authors would like to sincerely thank Dr. Kelly E Dooley from Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, and Dr. Joel Tarning from Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and Dr. Frank Kloprogge from Institute for Global Health, University College London, London, United Kingdom for providing details about the research and active discussions on the coding. We would like to thank Miss Hai-Ni Wen from Shanghai Chest Hospital and PhD candidate Xiao Qiu Liu for their critical comments. We would also like to thank Editage (www.editage.cn) for English language editing.

Declarations of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

J Li: Investigation, Data curation, Writing-Original draft, Writing-Reviewing and Editing, Visualization; X Cai: Investigation, Writing-Original draft, Writing- Reviewing and Editing; Y Chen: Writing-Reviewing and Editing, Supervision; C Wang: Methodology, Validation; Z Jiao: Conceptualization, Methodology, Writing- Reviewing and Editing, Supervision.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This paper was not funded.