Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Abstract

Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, = 17) or rifampin (600 mg/day, = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.).

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers

“…Bedaquiline elimination is complex and evidences an apparent oscillatory behavior. 16 This same oscillatory behavior is observed in the elimination of M2 and M3 (Figure 2). M2 time-concentration data are shown graphically in Figure 2A.…”

“…At the steady‐state sample collection on day 29, all subjects had received 10 days of either rifabutin or rifampin (days 20–29) in addition to 2 400‐mg bedaquiline doses (days 1 and 29). By day 29, all subjects were at steady state with respect to the rifamycins …”

“…17 Combining rifabutin with bedaquiline, which is approved in the United States for treatment of MDR pulmonary TB, is theoretically an attractive option for rifabutin-susceptible MDR TB. 17 Unlike rifampin and rifapentine, which accelerate bedaquiline clearance and reduce plasma levels by 45% to 50%, [14][15][16] rifabutin had little quantitative impact on bedaquiline exposure, 16 probably because it is not as strong an inducer of cytochrome P450 3A4 as the other 2 rifamycins. 11,12 The combination of rifabutin and bedaquiline yielded greater whole blood mycobactericidal activity than the sum of their separate effects, and the combined effect was sustained, whereas the mycobactericidal activity of rifampin and bedaquiline was not.…”

“…Here we report the effects of daily rifabutin dosing on bedaquiline desmethylation into M2 and M3 in healthy adult volunteers. The data were collected during a randomized phase 1 drug‐drug interaction trial that evaluated the safety, tolerability, and pharmacokinetics of bedaquiline when administered in combination with rifampin and rifabutin . The sponsor stipulated that the M2 and M3 data were not to be included in the report of the trial, as their quantification was not specified in the original protocol but was added after initiation of the trial; they are reported here.…”

“…14,15 As a result these 2 rifamycins are not recommended components of bedaquiline-containing multidrug treatment regimens. 14,15 In contrast to rifampin and rifapentine, rifabutin coadministration has little quantitative impact on bedaquiline concentrations, 16 but the effect of rifabutin, a component of treatment regimens for MDR TB, 17 on desmethylation of bedaquiline to M2 has not been reported, and there is no information in humans about how any rifamycin affects N-didesmethylation of M2 to M3. This information is needed for a thorough evaluation of the suitability of rifabutin as a component of bedaquiline-containing MDR-TB treatment regimens.…”