Current research toward optimizing dosing of first-line antituberculosis treatment

Figures & data

Table 1. Summary of sources of variability discussed in this article, with potential actions that could reduce pharmacokinetic variability.

Source of pharmacokinetic variability (section)	Potential actions mitigating pharmacokinetic variability
Drug formulation (2)	Independent bioequivalence testing against established standard comparator product. Quality surveillance of drug products used in programs. Development and implementation of protocols for regular testing of relative bioavailability in programs. Development of improved in vitro screening methods that predict bioavailability, for use in programs.
Weight and body composition (3)	Optimize pragmatic weight band-based dosing guidelines based on contemporary knowledge and pharmacokinetic evidence in adult and pediatric patient populations.
Other clinical covariates (4)	Pharmacokinetic studies to optimize dosing in infants, pregnant women, patients with renal or hepatic impairment, and other special populations.
Pharmacogenetic variation (5)	For clinically important genetic variants, development of field-friendly genetic tests to facilitate dosing by genotype. Population surveys to optimize dosing for the population based on the prevalence of clinically important genetic variants.
Drug-drug interactions (6)	Drug-drug interactions need to be considered and studied within antituberculosis regimens and between antituberculosis drugs and other commonly administered drugs. Studies should preferably be performed in patients. For clinically important pharmacokinetic drug-drug interactions, dose adjustment strategies should be evaluated in patients.
Dose preparation and administration (7)	Investment in the development of user- friendly formulations for children and adults with robust bioavailability under field conditions. The clinical importance, in the context of patients under field conditions, of food effects and other factors influencing bioavailability should be evaluated and if important should be addressed e.g. by developing formulations less vulnerable to food effects.
Laboratory error (8)	Laboratory participation in proficiency testing. Development of platforms for sharing assay methodologies and expertise.

Figure 1. Evaluation of WHO’s current weight band-based doses for the treatment of drug-sensitive TB. AUC to 24 h (AUC_0–24) for rifampin (Court R, Chirehwa MT, Wiesner L, Wright B, Smythe W, Kramer N, McIlleron H. Quality assurance of rifampin-containing fixed-drug combinations in South Africa: dosing implications. Int J Tuberc Lung Dis. 1 May 2018;22(5):537–543. Reprinted with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union), isoniazid, pyrazinamide and ethambutol, by weight band. Left-hand panel: Predicted AUC_0–24 when the currently recommended fixed dose combination tablets (rifampin/isoniazid/pyrazinamide/ethambutol 150/75/400/275 mg) are given according to the dosing guidelines for adults (<38 kg—2 tablets; 38–54.9 kg—3 tablets; 55–70 kg—4 tablets; >70 kg—5 tablets). Right-hand panel: Predicted AUC_0–24 when patients <55 kg are given an additional FDC to account for the higher CL/kg in smaller individuals (<38 kg—3 tablets; 38–54.9 kg—4 tablets; 55–70 kg—4 tablets; >70 kg—5 tablets).

Figure 1. (Continued).