PII-065 - OPTIMAL DOSING OF RIFAPENTINE IN NOVEL 4-MONTH HIGH-DOSE RIFAPENTINE WITH MOXIFLOXACIN REGIMEN FOR THE TREATMENT OF DRUG-SUSCEPTIBLE TUBERCULOSIS.

V. Chang¹, M. Imperial¹, R. Savic¹, A. Tuberculosis Trials Consortium²; ¹University of California, San Francisco, San Francisco, CA, USA, ²AIDS Clinical Trials Group and the Tuberculosis Trials Consortium, , USA.

Background: Study 31/A5349 (NCT02410772) was a phase 3 trial that demonstrated noninferiority of a 4-month rifapentine (RPT) plus moxifloxacin-based regimen compared to the 6-month standard treatment for drug-sensitive tuberculosis. We previously reported a RPT popPK and PKPD model, which identified low RPT exposure as a risk factor for TB-related unfavorable outcomes, particularly in the high-risk group (defined by high baseline disease burden). In this study we sought to evaluate PK-safety relationships and perform simulations to inform who can benefit from optimized RPT doses.

Methods: Model-derived AUC and Cmax, in addition to clinical and demographic factors, were tested in logistic regressions for on treatment grade 3-5 AEs (CTCAE version 4.3), tolerability, death, elevated ALT/AST, and serious AEs. Dosing strategies were simulated in NONMEM to assess proportion of patients reaching target exposure (570 µg∙h/mL) and experiencing TB-related unfavorable outcomes.

Results: Higher RPT AUC was only significantly associated with decreased risk for death (OR, 0.50 for +100 µg∙h/mL; 95% CI, 0.27 – 0.87). Overall mortality was low (7/1687).

Simulations suggested that with a 1500 and 1800 mg dose, 70% and 80% of all participants would reach the target exposure, respectively. Use of these higher doses would improve clinical outcome, primarily in the high-risk group where 10% of patients with a TB-related unfavorable outcome would decrease to 8% and 6%, respectively. Low risk patients would experience only a marginal benefit, decreasing from 2.5% to 2% and 1.5%, respectively.

Conclusion: Cure rates can be improved in high-risk patients by increasing RPT dose and exposure. The lack of PK-safety relationship suggests that higher doses for RPT might be safe and well tolerated, however this needs to be further confirmed in a clinical trial.

Dorman, S. E. et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med 384, 1705–1718 (2021).

Dorman, S. E. et al. High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemporary Clinical Trials 90, 105938 (2020).

World Health Organization. Treatment of drug-susceptible tuberculosis: rapid communication. (World Health Organization, 2021).