Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis

Ngwalero, Precious; Brust, James C.M.; Beek, Stijn W van; Wasserman, Sean; Maartens, Gary; Meintjes, Graeme; Joubert, Anton; Norman, Jennifer; Castel, Sandra; Gandhi, Neel R.; Denti, Paolo; McIlleron, Helen; Svensson, Elin M; Wiesner, Lubbe

doi:10.1128/aac.02399-20

Cited by 13 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compared with BDQ, the MIC value of WX-081 was generally equivalent to or marginally higher than BDQ. The pharmacokinetic study of BDQ demonstrated that C max was 1.715 μg/mL, 18 which is dozens of folds higher than common MIC values of the clinical isolates, and was usually much higher than the target effective plasma concentration, ie, 0.6 μg/mL. 19 Multiple species study with mouse and rat demonstrated that evidently higher serum concentrations and lung tissue concentrations were acquired for WX-081 than BDQ, despite being administered at the same dosage.…”

Section: Discussionmentioning

confidence: 99%

In vitro and Intracellular Antibacterial Activity of Sudapyridine (WX-081) Against Tuberculosis

Xiao¹,

Yu²,

Shang³

et al. 2023

IDR

View full text Add to dashboard Cite

Background Sudapyridine (WX-081) has exhibited equivalent efficacy than its counterpart parent drug bedaquiline (BDQ) but better safety profile against Mycobacterium tuberculosis ( Mtb ). Our study was aimed to evaluate in vitro activity of WX-081 against the clinical isolates of Mtb with different drug-resistance profiles and the intracellular bactericidal activity against the reference strain. Methods The minimum inhibitory concentrations (MICs) of WX-081 and BDQ were tested against 114 Mtb clinical isolates. The intracellular activity of WX-081 and BDQ against the Mtb reference strain H37Rv in THP-1 cells was also evaluated in parallel. Results The MICs for WX-081 of the enrolled isolates ranged from 0.0156 μg/mL to 1 μg/mL. The MIC 50 and MIC 90 of WX-081 were, respectively, 0.25 μg/mL and 0.5 μg/mL, with 95.6% of the enrolled strains having MICs ≤0.25 μg/mL. For a given strain, the MIC value of WX-081 was generally equivalent to or 2-fold than MIC of BDQ. The intracellular bacterial killing was acquired with the tested drug concentrations that were presumed attainable during clinical usage. Conclusion WX-081 exhibited potent efficacy against the clinical isolates in vitro. The intracellular killing effect of sudapyridine against the reference strain supports its potential efficacy in treating TB patients.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro and Intracellular Antibacterial Activity of Sudapyridine (WX-081) Against Tuberculosis

Xiao¹,

Yu²,

Shang³

et al. 2023

IDR

View full text Add to dashboard Cite

show abstract

“…Additional structural components were evaluated in a stepwise manner as suggested by the available data and prior knowledge. For instance, plasma concentrations of the primary metabolite of bedaquiline, M2, are of importance due to its relevance to safety concerns [ 16 , 17 ]. Therefore, mechanistic representation of the metabolism of bedaquiline to M2 was described using a liver compartment represented by the well-stirred liver model.…”

Section: Methodsmentioning

confidence: 99%

Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling

et al. 2023

View full text Add to dashboard Cite

Background Site-of-action concentrations for bedaquiline and pretomanid from tuberculosis patients are unavailable. The objective of this work was to predict bedaquiline and pretomanid site-of-action exposures using a translational minimal physiologically based pharmacokinetic (mPBPK) approach to understand the probability of target attainment (PTA). Methods A general translational mPBPK framework for the prediction of lung and lung lesion exposure was developed and validated using pyrazinamide site-of-action data from mice and humans. We then implemented the framework for bedaquiline and pretomanid. Simulations were conducted to predict site-of-action exposures following standard bedaquiline and pretomanid, and bedaquiline once-daily dosing. Probabilities of average concentrations within lesions and lungs greater than the minimum bactericidal concentration for non-replicating (MBC NR ) and replicating (MBC R ) bacteria were calculated. Effects of patient-specific differences on target attainment were evaluated. Results The translational modeling approach was successful in predicting pyrazinamide lung concentrations from mice to patients. We predicted that 94% and 53% of patients would attain bedaquiline average daily PK exposure within lesions (C avg -lesion) > MBC NR during the extensive phase of bedaquiline standard (2 weeks) and once-daily (8 weeks) dosing, respectively. Less than 5% of patients were predicted to achieve C avg -lesion > MBC NR during the continuation phase of bedaquiline or pretomanid treatment, and more than 80% of patients were predicted to achieve C avg -lung >MBC R for all simulated dosing regimens of bedaquiline and pretomanid. Conclusions The translational mPBPK model predicted that the standard bedaquiline continuation phase and standard pretomanid dosing may not achieve optimal exposures to eradicate non-replicating bacteria in most patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01217-7.

show abstract

“…Molar concentrations were used during model development to account for mass balance between bedaquiline and its metabolite M2. Participant albumin information were not captured in the current study, therefore we imputed a reported albumin concentration from a previous study in South African patients with RR‐TB 19 …”

Section: Methodsmentioning

confidence: 99%

“…Participant albumin information were not captured in the current study, therefore we imputed a reported albumin concentration from a previous study in South African patients with RR-TB. 19 When analysing the data, we first fit the original model as published, without re-estimating any of the population parameters, but using the study covariate, doses and dosing regimen information. This is similar to using the current data as an external validation of the model, i.e.…”

Section: Pk Modellingmentioning

confidence: 99%

Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin‐resistant tuberculosis

Court

Gausi

Mkhize

et al. 2022

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics (PK) and describe bedaquiline exposure in the breast milk of mothers treated for rifampicin-resistant tuberculosis (TB), where there are no human data available. Methods:We performed a longitudinal PK study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure.Pharmacokinetic sampling was performed at 4 time-points over 6 hours in the third trimester, and again at approximately 6 weeks postpartum. We obtained serial breast milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and nonbreastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the breast milk and plasma bedaquiline assays, and population PK modelling to interpret the bedaquiline concentrations.Results: We recruited 13 women, 6 of whom completed the ante-and postpartum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante-and postpartum bedaquiline exposures than reported in nonpregnant controls. Bedaquiline concentrations in breast milk were higher than maternal plasma (milk to maternal plasma ratio: 14:1). A single random plasma bedaquiline and M2 concentration was available in 4 infants (median age: 6.5 wk): concentrations in the 1 breastfed infant were similar to maternal plasma concentrations; concentrations in the 3 nonbreastfed infants were detectable but lower than maternal plasma concentrations. Conclusion:We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in breast milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.Richard Court and Kamunkhwala Gausi contributed equally to this study.

show abstract

Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis

Cited by 13 publications

References 41 publications

In vitro and Intracellular Antibacterial Activity of Sudapyridine (WX-081) Against Tuberculosis

In vitro and Intracellular Antibacterial Activity of Sudapyridine (WX-081) Against Tuberculosis

Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling

Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin‐resistant tuberculosis

Contact Info

Product

Resources

About