Model-informed evidence for rifapentine use in Chinese HIV-positive adults with latent tuberculosis: Assessing ethnic PK differences and interactions with ritonavir

Background Ethnic differences in rifapentine pharmacokinetics (PK) between Chinese and non-Chinese populations remain unclear. When co-administered for the treatment of HIV and latent TB infection (LTBI), rifapentine may alter the PK of ritonavir. However, clinical data on rifapentine use in HIV-positive Chinese individuals are still lacking. Methods Both "bottom-up" and "top-down" approaches were employed to evaluate potential ethnic differences in the PK of rifapentine. Rifapentine PK profiles in Chinese individuals with HIV were simulated using a published population pharmacokinetic (PopPK) model to inform the development of a physiologically based pharmacokinetic (PBPK) model tailored to this population. The potential impact of rifapentine on ritonavir PK was further assessed through clinical trial simulations that integrated PBPK models for both drugs. Results External validation demonstrated that the non-Chinese rifapentine PopPK model adequately characterized the PK in Chinese LTBI patients. The developed PBPK models for rifapentine in both non-Chinese and Chinese adults showed consistent performance with comparable PK parameters. Cross-validation further indicated that simulations from the Chinese PBPK model were in good agreement with predictions from the non-Chinese PopPK model. Clinical trial simulations using the PBPK models revealed that rifapentine had no significant impact on the steady-state exposure of ritonavir, with rifapentine reducing ritonavir AUC ss by approximately 9% and C max,ss by only 7%. Conclusion The integrated modeling strategy indicated that there are no clinically significant ethnic differences in the PK of rifapentine between Chinese and non-Chinese populations, and that dose adjustment of ritonavir is not necessary when co-administered with rifapentine. Trial registration ChiCTR2400089896 (date of registration: 19th September 2024).