Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study

S E T T I N G: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. O B J E C T I V E: To use physiologically based pharmacokinetic (PBPK) modelling to simulate potential LAI administration strategies for four anti-tuberculosis agents—isoniazid, rifapentine, bedaquiline and delamanid—in adults for treatment for latent tuberculous infection (LTBI). D E S I G N: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cutoff or minimum inhibitory concentration for the dosing interval. R E S U L T S: The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001–0.0025 h¹ and 0.0015–0.0025 h¹, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing. C O N C L U S I O N: We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.