Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

Abstract

e Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ϳ200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. R ifapentine (P), a cyclopentyl rifamycin with a much longer half-life than rifampin (R) (10 to 15 h compared to 2 to 5 h, respectively), was developed with the goal of allowing highly active once-weekly therapy for tuberculosis (TB) (37). However, relative to twice-or thrice-weekly rifampin-isoniazid (RH), once-weekly PH during the continuation phase of treatment was associated with greater drug-susceptible relapse among HIV-negative patients with lung cavitation (8) and a significant incidence of acquired rifamycin monoresistance among HIV-positive patients (35). Recent data in a murine model of active TB showed that increasing rifamycin exposure by daily dosing of P in place of R improved sterilizing activity, suggesting that daily P might permit shortening of treatment duration (28-30). These encouraging results prompted a large-scale phase 2 clinical trial conducted by the Tuberculosis Trials Consortium (TBTC study 29) to evaluate the safety and efficacy of a regimen in which P is substituted for R during the initial 8 weeks of treatment (13).P is known to have significantly higher intracellular accumulation relative to R, as the MIC and minimal bactericidal concentration (MBC) of P against Mycobacterium tuberculosis H37Rv within macrophages are 4-fold lower than the corresponding values against extracellular bacilli (22). On the other hand, the MIC and MBC of R against intracellular M. tu...

Delamanid Kills Dormant Mycobacteria In Vitro and in a Guinea Pig Model of Tuberculosis

“…In addition, the outcome for INH was similar to that in the report from Hoff et al (a 1.71-log reduction compared with an ϳ1.6-to 1.7-log reduction) (39). Similar differences in the outcomes in guinea pigs were also found for RIF when our data at a dose of 25 mg/kg were compared with those in a report of RIF at a dose of 50 mg/kg (40). The reason for different results among groups is unknown, but the methodological differences, such as bacterial strains, breeding conditions, and the time of initiation of the treatment, could be considerable.…”

Preliminary Pharmacokinetic Study of Repeated Doses of Rifampin and Rifapentine in Guinea Pigs

“…Steady-state PK values of RIF and RFP (Table 1) differed from those of single-dose studies (1,7). The C max and AUC were significantly increased at the steady state for both RFP and RIF compared to single-dose data.…”

“…The C max and AUC were significantly increased at the steady state for both RFP and RIF compared to single-dose data. In the present study, we determined metabolite concentrations from serum samples obtained in earlier single-dose studies (1) and found that desRFP was absent in guinea pigs that received a single dose of RFP of 10 or 50 mg/kg but present in 2 of 3 animals that received a single dose of 100 mg/kg. The guinea pig in which desRFP serum concentrations were undetectable following a single dose of RFP at 100 mg/kg was found to have significantly lower serum RFP concentrations than those of the other two animals receiving the same dose (data not shown).…”

“…We recently reported that substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen did not reduce the time required to cure guinea pigs with established Mycobacterium tuberculosis infection (1). This result may be quite important, as it contradicts similar studies in mice (2), but appears to corroborate recent findings from a clinical trial (TBTC Study 29) investigating the substitution of daily RFP for RIF in the first-line regimen for treatment of drug-susceptible tuberculosis (TB) (3).…”

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

“…Clinical trial simulations demonstrate that splitting the dose or taking the dose with food could substantially increase daily RFP exposures, which is a significant finding, given that RFP's activity appears to correlate best with AUC/MIC and that current dosing achieves concentrations that are still on the steep part of the dose-response curve. The dose-response relationship was reported in mouse studies (20), guinea pig studies (21), and patient early bactericidal activity studies (22). Most importantly, preliminary results from the recently completed phase IIb TBTC trial 29X in patients suggests a pronounced exposure-response relationship, where the time to culture conversion on solid and liquid media was best predicted by rifapentine exposure (23).…”