Penetration of Isoniazid, Rifampicin, Pyrazinamide and Moxifloxacin into Pulmonary TB Lesions in Rabbits
Maria C. Kjellsson(1,4), Veronique Dartois(2), Anne Goh (2), Laura Via(3), Steven Kern(4), Goonaseelan (Colin) Pillai(4)
1. Pharmacometrics Research Group, Uppsala University, Uppsala, Sweden; 2. Clinical Pharmacology, Novartis Institute of Tropical Diseases Pte Ltd, Singapore; 3. National Institutes of Health, Laboratory of Clinical Infectious Diseases, Tuberculosis Research Section, Bethesda, MD, USA; 4. Modeling & Simulation, Novartis Pharma AG, Basel, Switzerland.
Background: About one third of the world's population has latent tuberculosis (TB), whereof about nine million cases of active tuberculosis emerge annually and a majority of the cases being pulmonary TB (PTB) . An essential factor in halting the global increase in tuberculosis is effective treatment, with a combination of antimicrobial drugs against Mycobacterium Tuberculosis. Factors influencin response to treatment include the degree of drug penetration into the target tissue. Bacterial resistance development has been hypothesized to be dependent on drug penetration into TB lesions. With so many aspects of the TB treatment success being dependent on drug penetration into the site of action, it is surprising how little is known of the pharmacokinetics (PK) of anti-TB drugs inside PTB lesions. Patients with TB are known to have lung lesions that display diversity in size, location, structure and cellular/acellular content and physiochemical environment, with an associated difference in drug penetration.
Objective: In this study the PK and penetration of four anti-TB drugs into PTB lesions in rabbits was investigated. Covariates like lesion type and size was also explored.
Methods and data: Rabbits infected with TB were given isoniazid (INH), moxifloxacin (MXF), pyrazinamide (PZA) and rifampicin (RIF). Drugs were given in different regiments (multiple and single dosing) and at different time points, (from 0.5 h to 16 h) before sacrifice. Measurement were made of drug concentrations in healthy lung and PTB lesion tissue and also serial sampling of plasma was performed before time of sacrifice. PK into lesions and healthy lung was described using effect compartment models where the drug was assumed to partition to lesions and lung tissue from the central plasma compartment with an estimated delay. For the parameters related to penetration into the PTB lesions the impact of lesion size and type was investigated.
Results and conclusions: INH's and PZA's plasma PK in rabbits were best described using a 2-compartment model while MXF's and RIF's plasma PK were best described using a 1-compartment model. MXF showed the highest penetration into lesions of the four drugs.
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