Anthony J Garcia-Prats1,2, Elin M Svensson3,4, Jana Winckler1, Heather R Draper1, Lee Fairlie5, Louvina E van der Laan1, Masebole Masenya5, H Simon Schaaf1, Lubbe Wiesner6, Jennifer Norman6, Rob E Aarnoutse3, Mats O Karlsson4, Paolo Denti6, Anneke C Hesseling1. 1. 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. 2. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 2870 University Avenue, Suite 200, Madison, WI 53705, USA. 3. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen (864), The Netherlands. 4. Department of Pharmacy, Uppsala University, PO Box 580, 751 23 Uppsala, Sweden. 5. Wits Reproductive Health and HIV Institute Shandukani CRS, Faculty of Health Sciences, University of the Witwatersrand, 22 Esselen Street, Hilbrow 2001, South Africa. 6. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, K45 Old Main Building, Groote Schuur Hospital, Observatory, Cape Town 7925, South Africa.
Abstract
BACKGROUND: 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. OBJECTIVES: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. PATIENTS AND METHODS: 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]. RESULTS: 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. CONCLUSIONS: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
BACKGROUND: 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. OBJECTIVES: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. PATIENTS AND METHODS: 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]. RESULTS: 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. CONCLUSIONS: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
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