Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data

Citation: Rifat D, Prideaux B, Savic RM, Urbanowski ME, Parsons TL, Luna B, Marzinke MA, Ordonez AA, DeMarco VP, Jain SK, Dartois V, Bishai WR, Dooley KE. Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data. Sci Transl Med. 2018 Apr 4;10(435). pii: eaai7786. doi: 10.1126/scitranslmed.aai7786. PMID: 29618565. PMCID: PMC5969904.

Access full article:

https://www.ncbi.nlm.nih.gov/pubmed/29618565

In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.

Categories

CRS
Topics

Clinical Trials

A5225: Phase I/II Dose-Finding Study of High-Dose...

A5225/HiFLAC is a Phase I/II dose escalation and validation study of the safety, tolerability, and therapeutic effect of an...

Read More

A5322: Long-Term Follow-up of Older HIV-infected Adults in...

The A5322 protocol is a long-term observational study, with a planned series of analyses of data to be collected from an...

Read More

P1108: A Phase I/II, Open-Label, Single Arm Study to...

This purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in...

Read More

Identification of Biomarkers That Can Predict Progression...

Purpose: The C-TRIUMPH study has identified 20 household contacts (HHC), who have progressed to active TB from its HHCs cohort...

Read More

A5290, A Randomized, Phase 2b Study of a Double-Dose...

Rifampin (RIF), the cornerstone of TB treatment, has very problematic drug-drug interactions with PIs. The use of relatively...

Read More