Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

Winter, Helen; Egizi, Erica; Murray, Stephen R.; Erondu, Ngozi; Ginsberg, Ann M.; Rouse, Doris J.; Severynse-Stevens, Diana; Pauli, Elliott

doi:10.1128/aac.04171-14

Cited by 26 publications

(29 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…reported bedaquiline AUC 0–336h of 58 200 (42 200–78 200) ng ml –1 *h 18, and Winter et al . reported 67 200 (standard deviation 20 200) ng ml –1 *h 19, while the median in this study was 44 000 ng ml –1 *h. This might be explained by the larger proportion of black subjects included here (88%) compared to in the studies by Dooley and Winter (22% and 6%, respectively), since black race has been associated with higher bedaquiline clearance 16.…”

Section: Discussioncontrasting

confidence: 63%

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children

Svensson

Bois

Kitshoff

et al. 2018

Brit J Clinical Pharma

View full text Add to dashboard Cite

AimsBedaquiline is an important novel drug for treatment of multidrug‐resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short‐term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.MethodsA randomized, open‐label, two‐period cross‐over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed‐effects modelling. A questionnaire was used to assess palatability and acceptability.ResultsThere was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94–108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.ConclusionsThe bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug‐resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

show abstract

Section: Discussioncontrasting

confidence: 63%

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children

Svensson

Bois

Kitshoff

et al. 2018

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Rifamycins induce the CYP450 system, which is the pathway for metabolism of BDQ. Thus, RFB cotreatment may compromise therapy by accelerating drug clearance and lowering BDQ exposure (30). Notably, of the seven cases with microbiological relapse, six were cotreated with RFB.…”

Section: Discussionmentioning

confidence: 99%

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

Alexander

Vasireddy

et al. 2017

J Clin Microbiol

View full text Add to dashboard Cite

Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5. Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis. Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2-to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.

show abstract

“…Rifamycins are known inducers of CYP3A4; rifampin has the highest CYP3A4 induction potential, followed by rifapentine, and then rifabutin . As a result, rifamycin coadministration decreases exposure to other drugs metabolized via CYP3A4 and their associated metabolites, and both rifampin and rifapentine have been shown to reduce both serum bedaquiline concentrations and M2 concentrations when they are coadministered with bedaquiline . As a result these 2 rifamycins are not recommended components of bedaquiline‐containing multidrug treatment regimens …”

mentioning

confidence: 99%

“…11,12 As a result, rifamycin coadministration decreases exposure to other drugs metabolized via CYP3A4 and their associated metabolites, 13 and both rifampin and rifapentine have been shown to reduce both serum bedaquiline concentrations and M2 concentrations when they are coadministered with bedaquiline. 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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers

Healan

Salata

Griffiss

et al. 2018

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

There is an urgent need to identify safe and effective combination treatments for multidrug‐resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug‐resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N‐monodesmethyl metabolite, M2, and further desmethylated into an N‐didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20–41. In the rifabutin group maximum M2 concentrations (Cmax) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration‐time curve [AUC0‐τ]). Peak concentrations of M3 increased approximately 3‐fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0‐∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4‐fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.

show abstract

Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

Cited by 26 publications

References 13 publications

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers

Contact Info

Product

Resources

About