PT-012 - POPULATION PHARMACOKINETICS OF ISONIAZID IN TBTC STUDY 31/ACTG A5349.

M. Imperial¹, I. Cohen², R. Savic¹, A. Tuberculosis Trials Consortium³; ¹University of California, San Francisco, San Francisco, CA, USA, ²Denali Therapeutics, San Francisco, CA, USA, ³AIDS Clinical Trials Group and the Tuberculosis Trials Consortium, , USA.

Background: Isoniazid (INH) has the most potent early bactericidal activity of all anti-tuberculosis (TB) drugs but exhibits considerable variability in plasma that may have clinically important consequences. We performed largest population pharmacokinetic analysis of INH in patients with drug-susceptible TB using data from S31/A5349 (NCT02410772).

Methods: S31/A5349 compared two 4-month high-dose rifapentine-based regimens to the standard 6-month regimen. INH was flat-dosed at 300 mg once daily in each arm. Three (N=2270) or six (N=53) blood samples at steady state were planned for each participant. NONMEM was used to develop the PK model.

Results: A two-compartment model with first-order kinetics best described the INH data. A mixture model was used to describe two subpopulations on INH elimination (55% fast acetylators). Apparent clearance (CL/F) in the fast and slow acetylators were 27.4 L/h, (%relative standard error, RSE: 2) and 10.6 L/h (RSE: 4), respectively. Fast acetylators had longer mean absorption transit time (MTT) compared to slow acetylators (0.43 h, RSE: 6, vs 0.30 h, RSE: 9). MTT was 2.8-fold (RSE: 9) longer for the high-dose rifapentine-based arms compared to the standard arm, possibly due to 4-month arms taken with food and standard arm without food. Asian or Mixed compared to Black race (18% increase, RSE: 19) and higher weight (8% increase per 10 kg increase, RSE: 13) were significantly associated (P < 0.01) with higher CL/F, although contributing marginally to overall variability. Steady-state AUC following 300 mg flat-dose resulted in 9.4-fold variation, and suggested 89% of fast acetylators were below a target of 10.5 mgh/L1, while all slow acetylators were above target.

Conclusion: Current treatment guidelines may lead to underexposure in patients who are fast acetylators of INH.

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