Pharmacokinetics and Safety of Clofazimine in Children With Rifampicin-Resistant Tuberculosis

Abstract Background We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods Children aged <18 years were eligible. Clofazimine was administered by weight-based dosing. Sparse and semi-intensive pharmacoki...

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Vydané v:The Journal of infectious diseases Ročník 231; číslo 5; s. e873 - e881
Hlavní autori: Hughes, Jennifer A, Solans, Belén P, Garcia-Prats, Anthony J, Draper, Heather R, Schaaf, H Simon, Nielsen, James C, Nortier, Elri, Courtney, Ingrid, Palmer, Megan, van der Laan, Louvina, Savic, Radojka M, Hesseling, Anneke C
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: US Oxford University Press 15.05.2025
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ISSN:0022-1899, 1537-6613, 1537-6613
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Abstract Abstract Background We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods Children aged <18 years were eligible. Clofazimine was administered by weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline and weeks 2 and 16. Clofazimine weekly area under the concentration time-curve (wAUC) was compared with the target wAUC (60.87 mg × h/L and 111.79 mg × h/L) in adults receiving clofazimine (100 mg) daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT interval prolongation and laboratory assessment. Results Twenty children were included: median age was 6.0 years (IQR, 1.6–14.4); 6 (30%) were male. Median clofazimine wAUC was 162.94 (IQR, 130.06–263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR, 81.9–151.9). No serious or grade ≥3 cardiac events occurred. There was a QT interval increase of 0.02 milliseconds for every 1-µg/L increase in clofazimine concentration. One severe adverse event (elevated alanine transferase) led to temporary withdrawal of clofazimine. Conclusions The clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Clinical Trials Registration South African National Clinical Trials Register (https://sanctr.samrc.ac.za/; DOH-27-0620-6415). We investigated the pharmacokinetics and safety of clofazimine in children routinely treated for rifampicin-resistant tuberculosis. Semi-intensive and sparse sampling was completed. Clofazimine exposures were considerably higher than protocol-specified adult targets, with a linear relationship observed between clofazimine concentrations and increasing QT interval.
AbstractList Paediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB).BACKGROUNDPaediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB).Children <18 years being routinely treated for MDR/RR-TB were eligible for study participation. Soft gel capsules (Novartis Pharma AG) were administered using WHO-recommended weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline, Week 2 and 16. Clofazimine weekly area-under-the-concentration-time-curve (wAUC) was compared to target wAUC (60.87 mg*h/L and 111.79 mg*h/L) in adults receiving clofazimine 100mg daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT-interval prolongation and laboratory assessment.METHODSChildren <18 years being routinely treated for MDR/RR-TB were eligible for study participation. Soft gel capsules (Novartis Pharma AG) were administered using WHO-recommended weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline, Week 2 and 16. Clofazimine weekly area-under-the-concentration-time-curve (wAUC) was compared to target wAUC (60.87 mg*h/L and 111.79 mg*h/L) in adults receiving clofazimine 100mg daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT-interval prolongation and laboratory assessment.Twenty children, six (30%) male, median age 6.0 years (range, 1.6-14.4), were included. Median clofazimine wAUC was 162.94 (IQR 130.06-263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR 81.9-151.9). No serious or grade ≥3 cardiac events occurred. There was a linear relationship between clofazimine concentration and QT-interval prolongation with an increase of 0.02 ms for every µg/L. There were 59 adverse events at least possibly related to clofazimine; one severe adverse event (elevated ALT) led to temporary withdrawal of clofazimine.RESULTSTwenty children, six (30%) male, median age 6.0 years (range, 1.6-14.4), were included. Median clofazimine wAUC was 162.94 (IQR 130.06-263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR 81.9-151.9). No serious or grade ≥3 cardiac events occurred. There was a linear relationship between clofazimine concentration and QT-interval prolongation with an increase of 0.02 ms for every µg/L. There were 59 adverse events at least possibly related to clofazimine; one severe adverse event (elevated ALT) led to temporary withdrawal of clofazimine.Clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT-interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Lower clofazimine doses to achieve appropriate clofazimine exposures should be investigated in children using different drug formulations and harmonised weight bands.CONCLUSIONSClofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT-interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Lower clofazimine doses to achieve appropriate clofazimine exposures should be investigated in children using different drug formulations and harmonised weight bands.
We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Children aged <18 years were eligible. Clofazimine was administered by weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline and weeks 2 and 16. Clofazimine weekly area under the concentration time-curve (wAUC) was compared with the target wAUC (60.87 mg × h/L and 111.79 mg × h/L) in adults receiving clofazimine (100 mg) daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT interval prolongation and laboratory assessment. Twenty children were included: median age was 6.0 years (IQR, 1.6-14.4); 6 (30%) were male. Median clofazimine wAUC was 162.94 (IQR, 130.06-263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR, 81.9-151.9). No serious or grade ≥3 cardiac events occurred. There was a QT interval increase of 0.02 milliseconds for every 1-µg/L increase in clofazimine concentration. One severe adverse event (elevated alanine transferase) led to temporary withdrawal of clofazimine. The clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. South African National Clinical Trials Register (https://sanctr.samrc.ac.za/; DOH-27-0620-6415).
Abstract Background We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods Children aged <18 years were eligible. Clofazimine was administered by weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline and weeks 2 and 16. Clofazimine weekly area under the concentration time-curve (wAUC) was compared with the target wAUC (60.87 mg × h/L and 111.79 mg × h/L) in adults receiving clofazimine (100 mg) daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT interval prolongation and laboratory assessment. Results Twenty children were included: median age was 6.0 years (IQR, 1.6–14.4); 6 (30%) were male. Median clofazimine wAUC was 162.94 (IQR, 130.06–263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR, 81.9–151.9). No serious or grade ≥3 cardiac events occurred. There was a QT interval increase of 0.02 milliseconds for every 1-µg/L increase in clofazimine concentration. One severe adverse event (elevated alanine transferase) led to temporary withdrawal of clofazimine. Conclusions The clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Clinical Trials Registration South African National Clinical Trials Register (https://sanctr.samrc.ac.za/; DOH-27-0620-6415). We investigated the pharmacokinetics and safety of clofazimine in children routinely treated for rifampicin-resistant tuberculosis. Semi-intensive and sparse sampling was completed. Clofazimine exposures were considerably higher than protocol-specified adult targets, with a linear relationship observed between clofazimine concentrations and increasing QT interval.
Author Nielsen, James C
Courtney, Ingrid
Solans, Belén P
Garcia-Prats, Anthony J
Hesseling, Anneke C
Schaaf, H Simon
Palmer, Megan
Savic, Radojka M
Nortier, Elri
Hughes, Jennifer A
van der Laan, Louvina
Draper, Heather R
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Keywords pharmacokinetics
clofazimine
children
safety
tuberculosis
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The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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Snippet Abstract Background We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis...
We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Children aged <18...
Paediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children...
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StartPage e873
SubjectTerms Adolescent
Antitubercular Agents - administration & dosage
Antitubercular Agents - adverse effects
Antitubercular Agents - pharmacokinetics
Antitubercular Agents - therapeutic use
Child
Child, Preschool
Clofazimine - administration & dosage
Clofazimine - adverse effects
Clofazimine - pharmacokinetics
Clofazimine - therapeutic use
Female
Humans
Infant
Male
Rifampin - pharmacology
Rifampin - therapeutic use
Tuberculosis, Multidrug-Resistant - drug therapy
Title Pharmacokinetics and Safety of Clofazimine in Children With Rifampicin-Resistant Tuberculosis
URI https://www.ncbi.nlm.nih.gov/pubmed/39932891
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