A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy

Abstract

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens.

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

“…Compared with control group, the risk of ATLI can be reduced by 0.122 to 0.799 times. This is consistent with the findings put forth by Ng CS et al At present, PharmGKB has listed NAT2 as a genomic marker for isoniazid individualized drug treatment and recommended to detect the genotype of NAT2 before using isoniazid. It has been reported that administration under the guidance of NAT2 genotype can significantly reduce liver injury and the failure rate of early treatment caused by isoniazid .…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Although dosing stratified by NAT2 genotype has resulted in lower rates of toxicity and improved efficacy in patient with DS-TB [74], it is in patients with DR-TB that stratified dosing would play a more important role. High doses of isoniazid (10-15 mg/kg daily) are necessary to overcome strains of M. tuberculosis strains with low levels of resistance to isoniazid, which are associated with inhA gene mutations [75][76][77]. However, slow acetylators are at risk of toxicity when increased doses of isoniazid are prescribed and rapid acetylators may need even higher doses for optimal efficacy [75][76][77][78].…”

“…High doses of isoniazid (10-15 mg/kg daily) are necessary to overcome strains of M. tuberculosis strains with low levels of resistance to isoniazid, which are associated with inhA gene mutations [75][76][77]. However, slow acetylators are at risk of toxicity when increased doses of isoniazid are prescribed and rapid acetylators may need even higher doses for optimal efficacy [75][76][77][78]. Dose adjusting strategies have been proposed based on the presence of inhA or katG mutations in Mycobacterium tuberculosis [79].…”

“…Ethambutol AUC achieved with dosing approach: 30-37 kg (825 mg), 38-54 kg (1100 mg), 55-70 kg (1100 mg) and > 70 kg (1375 mg). proposed doses should be confirmed in slow and rapid acetylators, and the marked geographic variation in the distribution of NAT2 genotypes should be considered when optimizing doses [76,77,79]. While several SNPs in the NAT2 gene are used to categorize the genotype into slow, intermediate, and rapid acetylator types according to their number of functional NAT2 alleles, the identification and validation of a NAT2 tag SNP would simplify the development of genetic tests separating slow from intermediate and rapid acetylators [80,81].…”

Halloysite nanotubes as tools to improve the actual challenge of fixed doses combinations in tuberculosis treatment

“…1 TB treatment is based on a combination of four first-line tuberculostatic drugs and among them, INH is the most widely used and plays a crucial role based on its numerous advantages, as high early bactericidal activity, high selectivity to Mycobacterium tuberculosis and excellent bacteriostatic capacity with a minimum inhibitory concentration (MIC) of about 0.05-0.1 μg/mL. 2,3 Despite its crucial importance (INH is included in the WHO Model List of Essential Medicines), 4 only low levels of INH gain access into plasma via oral route, due to its poor intestinal permeability, rapid and extensive hepatic metabolism and short plasma halflife (1-4 h). 5 To achieve therapeutic effects, repetitive and high doses are therefore required, leading to severe adverse effects, such as hepatotoxicity and neuropathy.…”