Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?

ABSTRACT

Introduction: WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance.

Areas covered: This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity. Pharmacodynamic implications of optimized drugs and new options regimens are reviewed. Moreover a specific session describes innovative investigations on drug penetration.

Expert opinion: The optimal use of available antitubercular drugs is paramount for tuberculosis control and eradication. Whilst trials are still on-going, higher rifampicin doses should be reserved to treatment for tubercular meningitis. Therapeutic Drug Monitoring with limiting sampling strategies is advised in patients at risk of failure or with slow treatment response. Further studies are needed in order to provide definitive recommendations of pharmacogenetic-based individualization: however lower isoniazid doses in NAT2 slow acetylators and higher rifampicin doses in individuals with SLCO1B1 loss of function genes are promising strategies. Finally in order to inform tailored strategies we need more data on tissue drug penetration and pharmacological modelling.

KEYWORDS:

• Tuberculosis
• SLCO1B1
• high-dose rifampicin
• lesion penetration
• therapeutic drug monitoring
• acetylator status

Article highlights

• Inter- and intraindividual variability in the pharmacokinetics of antitubercular agents might have a role in explaining high variability of response, the likelihood of drugs’ underexposure, the high prevalence of drug-related toxicity and the selection of multi drug-resistant strains.

• Currently used rifampicin doses are suboptimal and trials investigating the effectiveness of increased dosing are on-going. Moreover the potential role of pyrazinamide in shortening treatment duration, due to its great sterilizing activity, is encouraging to design new regimens after the failure of trials with fluoroquinolones.

• Pharmacogenetic studies observed an association between SLCO1B1 genetic polymorphism (rs4149032) and reduced rifampicin concentrations. A NAT2-guided trial reported less isoniazid related liver injury and treatment failures.

• Lesion and intracellular drugs penetration may contribute to treatment outcomes like incidence of relapse, or of phenotypic drug resistance development.

• Innovative regimens with new agents and optimized use of drugs are highly needed, especially targeting improved safety, efficacy and PK/PD characteristics of drugs; research on pharmacokinetics in special populations are warranted to better define an individualized treatment approach.

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Declaration 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.

Additional information

Funding

This paper is not funded