Clofazimine pharmacokinetics in patients with TB: dosing implications. Tareq Abdelwahab, M., Wasserman, S., M Brust, J. C, Gandhi, N. R, Meintjes, G. A, Everitt, D., Diacon, A., Dawson, R., Wiesner, L., Svensson, E. M, Maartens, G., & Denti, P. Journal of Antimicrobial Chemotherapy, 75(11):3269–3277, Oxford University Press (OUP), 2020. ![Clofazimine pharmacokinetics in patients with TB: dosing implications [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
@article{TareqAbdelwahab2020,
abstract = {Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57{\%}) had drug-resistant TB and 54 (39{\%}) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.},
author = {{Tareq Abdelwahab}, Mahmoud and Wasserman, Sean and {M Brust}, James C and Gandhi, Neel R and Meintjes, Graeme A and Everitt, Daniel and Diacon, Andreas and Dawson, Rodney and Wiesner, Lubbe and Svensson, Elin M and Maartens, Gary and Denti, Paolo},
doi = {10.1093/jac/dkaa310},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tareq Abdelwahab et al. - 2020 - Clofazimine pharmacokinetics in patients with TB dosing implications.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,body fat,clofazimine,drug loading dose,exposure,fund{\_}ack,half-life,original,patient disposition,pharmacokinetics,plasma,plasma drug concentration,tuberculosis},
mendeley-tags = {OA,fund{\_}ack,original},
number = {11},
pages = {3269--3277},
pmid = {32747933},
publisher = {Oxford University Press (OUP)},
title = {{Clofazimine pharmacokinetics in patients with TB: dosing implications}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkaa310/5880203},
volume = {75},
year = {2020}
}
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Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a long elimination half-life. 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