A Systematic Review and Meta-analysis of Isoniazid Pharmacokinetics in Healthy Volunteers and Patients with Tuberculosis

Abstract

Purpose: This systematic review and meta-analysis assesses the pharmacokinetic (PK) summary estimates of isoniazid (INH) between healthy volunteers and patients with tuberculosis (TB), evaluates whether the current INH dose regimen is appropriate in patients with TB, and evaluates the impact of N-acetyl-transferase-2 (NAT2) status on the PK properties of INH.

Methods: A systematic approach was conducted to find studies with relevant INH PK data published in the English language up to February 2018. The PK properties of INH were extracted with their respective INH dosages and were dose normalized to allow a fair comparison between healthy volunteers and patients with TB. Meta-analysis was then performed for the C_max and AUC estimates for all INH dosages.

Findings: Ninety studies were included in this systematic review. TB status significantly affected the INH C_max and AUC estimates. In healthy volunteers, the dose-normalized INH C_max and AUC were statistically higher than those of patients with TB. No significant differences were found in dose-normalized C_max and AUC between adults with TB and adults with TB/HIV; however, the AUC in pediatric patients was significantly different between patients with TB and patients with TB/HIV. In addition, no significance was observed comparing the dose-normalized C_max and AUC of pediatric patients with TB and TB/HIV with their respective adult counterparts. Dose-normalized INH C_max and AUC in patients with fast and intermediate NAT2 were significantly lower than in patients with slow NAT2.

Implications: The current recommended dosages of INH were found to produce less drug exposure in patients with TB when compared with healthy volunteers. NAT2 polymorphism greatly impacts the PK properties of INH; hence, testing for acetylator status is highly recommended, and therapeutic drug monitoring would help reduce INH toxicity.

Keywords: isoniazid; meta-analysis; pharmacokinetics; systemic review; tuberculosis.