Rifapentine

Qian X, et al. identified rifapentine, a rifamycin antibiotic, as a potent inhibitor of yellow fever virus (YFV) using a high-throughput screening approach. In multiple cell lines, rifapentine demonstrated antiviral activity by interfering with both viral entry—specifically attachment to target cells—and replication. Mechanistic studies using a YFV replicon system and surface plasmon resonance revealed that rifapentine binds to the RNA-dependent RNA polymerase (RdRp) domain of the viral NS5 protein, likely interacting with its active site. In YFV-infected mouse models (both immunocompromised A129⁻/⁻ and wild-type C57 mice), rifapentine significantly improved survival, reduced viral load, alleviated clinical signs, and decreased organ injury. The antiviral effect was robust in both prophylactic and therapeutic regimens and exceeded that of sofosbuvir, a previously described YFV inhibitor.

Fig. 1 Antiviral activity of rifamycins on YFV and other flaviviruses. (Qian X, et al., 2022)

Pham MM, et al. used data from 185 HIV-positive participants in the BRIEF-TB/A5279 trial to characterize rifapentine disposition and optimize dosing for tuberculosis prevention. A one-compartment model with one-way conversion to its metabolite described the data well. Rifapentine absorption nearly doubled under fed conditions compared to fasting states. Clearance was increased by 31% in patients receiving efavirenz-based versus nevirapine-based antiretroviral therapy. Simulations demonstrated that weight-based dosing (10 mg/kg) resulted in lower drug exposures compared to fixed dosing, with 26–62% of simulated exposures in lower weight classes falling below the target. Fixed 600 mg daily dosing achieved target exposures in 85% of participants across all weight classes.

Fig. 2 Rifapentine and 25-desacetyl rifapentine concentrations. (Pham MM, et al, 2022)