Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial
Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. The Opti-Rif trial enrolled...
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| Veröffentlicht in: | Journal of antimicrobial chemotherapy Jg. 76; H. 12; S. 3237 |
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| Sprache: | Englisch |
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12.11.2021
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| Abstract | Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.
To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.
The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose].
Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure.
High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks. |
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| AbstractList | Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.BACKGROUNDRifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.OBJECTIVESTo characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose].PATIENTS AND METHODSThe Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose].Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure.RESULTSSixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure.High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.CONCLUSIONSHigh rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks. Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose]. Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks. |
| Author | Fairlie, Lee Garcia-Prats, Anthony J Karlsson, Mats O Norman, Jennifer Masenya, Masebole Draper, Heather R Denti, Paolo Hesseling, Anneke C Schaaf, H Simon Aarnoutse, Rob E Svensson, Elin M van der Laan, Louvina E Wiesner, Lubbe Winckler, Jana |
| Author_xml | – sequence: 1 givenname: Anthony J orcidid: 0000-0002-9280-1950 surname: Garcia-Prats fullname: Garcia-Prats, Anthony J organization: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 2870 University Avenue, Suite 200, Madison, WI 53705, USA – sequence: 2 givenname: Elin M surname: Svensson fullname: Svensson, Elin M organization: Department of Pharmacy, Uppsala University, PO Box 580, 751 23 Uppsala, Sweden – sequence: 3 givenname: Jana surname: Winckler fullname: Winckler, Jana organization: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa – sequence: 4 givenname: Heather R surname: Draper fullname: Draper, Heather R organization: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa – sequence: 5 givenname: Lee surname: Fairlie fullname: Fairlie, Lee organization: Wits Reproductive Health and HIV Institute Shandukani CRS, Faculty of Health Sciences, University of the Witwatersrand, 22 Esselen Street, Hilbrow 2001, South Africa – sequence: 6 givenname: Louvina E surname: van der Laan fullname: van der Laan, Louvina E organization: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa – sequence: 7 givenname: Masebole surname: Masenya fullname: Masenya, Masebole organization: Wits Reproductive Health and HIV Institute Shandukani CRS, Faculty of Health Sciences, University of the Witwatersrand, 22 Esselen Street, Hilbrow 2001, South Africa – sequence: 8 givenname: H Simon orcidid: 0000-0001-5755-4133 surname: Schaaf fullname: Schaaf, H Simon organization: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa – sequence: 9 givenname: Lubbe orcidid: 0000-0002-9070-8699 surname: Wiesner fullname: Wiesner, Lubbe organization: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa – sequence: 10 givenname: Jennifer surname: Norman fullname: Norman, Jennifer organization: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa – sequence: 11 givenname: Rob E surname: Aarnoutse fullname: Aarnoutse, Rob E organization: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen , The Netherlands – sequence: 12 givenname: Mats O surname: Karlsson fullname: Karlsson, Mats O organization: Department of Pharmacy, Uppsala University, PO Box 580, 751 23 Uppsala, Sweden – sequence: 13 givenname: Paolo surname: Denti fullname: Denti, Paolo organization: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa – sequence: 14 givenname: Anneke C surname: Hesseling fullname: Hesseling, Anneke C organization: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa |
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| Copyright | The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. |
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| Title | Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial |
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