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

Rajoli, RKR ORCID: 0000-0002-6015-5712, Podany, AT, Moss, DM, Swindells, S, Flexner, C, Owen, A ORCID: 0000-0002-9819-7651 and Siccardi, M ORCID: 0000-0002-3539-7867 (2018) Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, 22 (8). pp. 937-944.

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	physiologically based pharmacokinetic, pharmacokinetics, anti-tuberculosis, long-acting, intramuscular
Depositing User:	Symplectic Admin
Date Deposited:	14 Sep 2018 13:06
Last Modified:	19 Jan 2023 01:17
DOI:	10.5588/ijtld.17.0515
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3026219