Rajoli RKR, PodanyAT, Moss DM, et al. Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. Int J Tuberc Lung Dis. 2018 Aug 1;22(8):937-944. PMID: 29991405; PMCID: PMC6166436.
SETTING: 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.
OBJECTIVE:
niazid, rifapentine, bedaquiline and delamanid—in adults for treatment for latent tuberculous infection (LTBI).
DESIGN:
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 cut-off or minimum inhibitory concentration for the dosing interval.
RESULTS:
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 h−1 and 0.0015–0.0025 h−1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.
CONCLUSION:
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.