Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study. Denti, P., Wasmann, R. E, van Rie, A., Winckler, J., Bekker, A., Rabie, H., Hesseling, Anneke, C, van der Laan, L. E, Gonzalez-Martinez, C., Zar, H. J, Davies, G., Wiesner, L., Svensson, E. M, & McIlleron, H. M Clinical Infectious Diseases, 75(1):141–151, oct, 2022. ![Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Background In 2010, the WHO revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) table of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg , and suggest a new FDC with revised weight-bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42% female; 13.9% HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children \textless6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in \textless3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight-bands.
@article{Denti2021,
abstract = {Background In 2010, the WHO revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) table of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg , and suggest a new FDC with revised weight-bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42{\%} female; 13.9{\%} HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50{\%} lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children {\textless}6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in {\textless}3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight-bands.},
author = {Denti, Paolo and Wasmann, Roeland E and van Rie, Annelies and Winckler, Jana and Bekker, Adrie and Rabie, Helena and {Hesseling, Anneke}, C and van der Laan, Louvina E and Gonzalez-Martinez, Carmen and Zar, Heather J and Davies, Gerry and Wiesner, Lubbe and Svensson, Elin M and McIlleron, Helen M},
doi = {10.1093/CID/CIAB908},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Denti et al. - 2022 - Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients wit.pdf:pdf},
journal = {Clinical Infectious Diseases},
keywords = {OA,child,exposure,fund{\_}not{\_}ack,isoniazid,original,pediatrics,pyrazinamide,rifampin,tablet dosage form,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {oct},
number = {1},
pages = {141--151},
pmid = {34665866},
title = {{Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab908/6403131},
volume = {75},
year = {2022}
}
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Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42% female; 13.9% HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children \\textless6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in \\textless3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight-bands.","author":[{"propositions":[],"lastnames":["Denti"],"firstnames":["Paolo"],"suffixes":[]},{"propositions":[],"lastnames":["Wasmann"],"firstnames":["Roeland","E"],"suffixes":[]},{"propositions":["van"],"lastnames":["Rie"],"firstnames":["Annelies"],"suffixes":[]},{"propositions":[],"lastnames":["Winckler"],"firstnames":["Jana"],"suffixes":[]},{"propositions":[],"lastnames":["Bekker"],"firstnames":["Adrie"],"suffixes":[]},{"propositions":[],"lastnames":["Rabie"],"firstnames":["Helena"],"suffixes":[]},{"propositions":[],"lastnames":["Hesseling, Anneke"],"firstnames":["C"],"suffixes":[]},{"propositions":["van","der"],"lastnames":["Laan"],"firstnames":["Louvina","E"],"suffixes":[]},{"propositions":[],"lastnames":["Gonzalez-Martinez"],"firstnames":["Carmen"],"suffixes":[]},{"propositions":[],"lastnames":["Zar"],"firstnames":["Heather","J"],"suffixes":[]},{"propositions":[],"lastnames":["Davies"],"firstnames":["Gerry"],"suffixes":[]},{"propositions":[],"lastnames":["Wiesner"],"firstnames":["Lubbe"],"suffixes":[]},{"propositions":[],"lastnames":["Svensson"],"firstnames":["Elin","M"],"suffixes":[]},{"propositions":[],"lastnames":["McIlleron"],"firstnames":["Helen","M"],"suffixes":[]}],"doi":"10.1093/CID/CIAB908","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Denti et al. - 2022 - Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients wit.pdf:pdf","journal":"Clinical Infectious Diseases","keywords":"OA,child,exposure,fund_not_ack,isoniazid,original,pediatrics,pyrazinamide,rifampin,tablet dosage form,tuberculosis","mendeley-tags":"OA,fund_not_ack,original","month":"oct","number":"1","pages":"141–151","pmid":"34665866","title":"Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study","url":"https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab908/6403131","volume":"75","year":"2022","bibtex":"@article{Denti2021,\r\nabstract = {Background In 2010, the WHO revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) table of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg , and suggest a new FDC with revised weight-bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42{\\%} female; 13.9{\\%} HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50{\\%} lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children {\\textless}6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in {\\textless}3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. 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