EP-016 - GATIFLOXACIN EXPOSURE IN THE LESION AS TARGET SITE OF GATIFLOXACIN IN A RABBIT MODEL OF TUBERCULOSIS: COMPARISON WITH THE OUTCOMES FROM THE PHASE III OFLOTUB TRIAL.

L. Flori^1,2, J. Ernest¹, M. Zimmerman³, V. Dartois⁴, R. Savic¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²University of Pisa, Pisa, Tuscany, Italy, ³Hackensack Meridian Health, Hackensack, NJ, USA, ⁴Hackensack Meridian Health, Nutley, NJ, USA.

Background: The long durations of regimens for tuberculosis (TB) often lead to low patient compliance, resulting in the development of drug-resistant tuberculosis (DR-TB). Understanding how drugs reach lesion sites is critical to treatment optimization. To that aim, lesion penetration of gatifloxacin (GTX), a fluoroquinolone useful for the treatment of DR-TB, was investigated in rabbits to predict lesion exposure in the OFLOTUB trial patients.

Methods: 17 TB-infected and 11 uninfected rabbits were dosed orally with 30-100 mg/kg GTX for up to 15 days. GTX was quantified in plasma, and in normal lung, cellular lesions, and caseum, respectively. A plasma-to-tissue population pharmacokinetic (PK) model was developed in NONMEM (v7.5.1). Site-of-action exposure results were compared to outcome data from the Phase III OFLOTUB trial.

Results: The PK was best described by a two-compartment model with non-linear (Michaelis-Menten) elimination. TB-infected animals had significantly higher clearance than uninfected (25.1 and 11.4 L/h respectively). GTX penetrated well from plasma into the lesions with highest ratio in cellular lesion (RCL = 8.97) followed by lung (RL = 7.49) and caseum (RCA = 4.62). The lower site-of-action exposure in caseum compared to cellular lesions might reflect the finding that patients with cavities, showing a lower target site exposure and therefore less drug effect, were more likely to have an unfavorable outcome in the OFLOTUB trial.

Conclusion: This work showed GTX exposure at the target site for the first time, allowing the prediction of the penetration of GTX in the different types of lesions, supporting identifying the optimal dosage to maximize lesion exposure and therefore optimal therapeutic efficacy.