PT-006 - A LESION-CENTRIC AND TARGET-SPECIFIC PKPD MODEL OF PYRAZINOIC ACID IN PATIENTS WITH TUBERCULOSIS.

A. Fochesato^1,2,3, J. Ernest¹, V. Dartois⁴, R. Savic¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Rovereto, Trentino-Alto Adige, Italy, ³University of Trento, Trento, Trentino-Alto Adige, Italy, ⁴Hackensack Meridian Health, Nutley, NJ, USA.

Background: Pyrazinamide (PZA) and its active metabolite, pyrazinoic acid (POA), are pillars of anti-tuberculosis (TB) treatments, although their mode of action is still unclear. Recently, the Mycobacterium tuberculosis’ PanD enzyme has been proposed as a new molecular target specific of POA. Thus, quantifying POA at site-of-action is pivotal to help decipher drug mechanisms and guide patient-tailored treatment decisions. This work aims to develop the first lesion-centric and target-specific pharmacokinetic/pharmacodynamic (PKPD) model of POA in TB patients.

Methods: Fifteen patients received one dose of PZA (1500 mg), isoniazid, rifampicin, kanamycin, and moxifloxacin before scheduled lung resection. PK data in plasma, lungs, and lesions were acquired via liquid chromatography-mass spectrometry and laser capture microdissection. Data were modeled via nonlinear mixed effect techniques in NONMEM 7.5 to build a full population PK model relating PZA and POA.

Results: Plasma PK of POA was best described in tandem with PZA by a 1-compartment model with first order absorption and elimination. POA concentration was 4-7.5-fold lower than PZA in same lesions at steady state, partly explained by a shifted PK profile. POA plasma-to-lesion ratios ranged from 0.6-1, outlying a modest, yet comparable, accumulation across lesions. Scaling the lesion concentration by intrabacterial drug uptake and coupling an in vitro Emax model, POA inhibited the PanD activity up to ~ 55% on average.

Conclusion: Model findings suggest pathogen microbiological readouts’ central role in stratifying treatment efficacy as POA penetrates similarly in lesions. In addition, the proposed model-based approach can explore the correlation between PZA dosage and PanD activity to improve TB treatment.