{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tikiso T"],"funding":["Department for International Development, UK","Eunice Kennedy Shriver National Institute of Child Health and Human Development","Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group","NICHD NIH HHS","NIAID NIH HHS","ACTG","Adult Clinical Trial Group","National Institutes of Health","IMPAACT","National Institute of Allergy and Infectious Diseases","French Development Agency","Medical Research Council","National Institute of Mental Health","TB Alliance","Wellcome Trust","UBS Optimus Foundation"],"pagination":["1949-1959"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9633720"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["77(7)"],"pubmed_abstract":["<h4>Objectives</h4>Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population.<h4>Methods</h4>We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%).<h4>Results</h4>Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older.<h4>Conclusions</h4>To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation."],"journal":["The Journal of antimicrobial chemotherapy"],"pubmed_title":["Population pharmacokinetics of ethambutol in African children: a pooled analysis."],"pmcid":["PMC9633720"],"funding_grant_id":["UM1 AI106701","R01HD069175","MR/L004445/1","AI068632","UM1 AI068634","UM1 AI068636","R01 HD069175","S003410","206379/Z/17/Z","U01 AI068632","MC_UU_12023/26"],"pubmed_authors":["Tikiso T","Zar HJ","Lee J","Abdelwahab MT","Wiesner L","Andrieux-Meyer I","Rabie H","McIlleron H","Cotton MF","Hesseling A","Chabala C","Denti P","Davies G","Bekker A"],"additional_accession":[]},"is_claimable":false,"name":"Population pharmacokinetics of ethambutol in African children: a pooled analysis.","description":"<h4>Objectives</h4>Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population.<h4>Methods</h4>We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%).<h4>Results</h4>Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older.<h4>Conclusions</h4>To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jun","modification":"2025-04-21T16:57:34.494Z","creation":"2025-04-05T12:33:41.497Z"},"accession":"S-EPMC9633720","cross_references":{"pubmed":["35466379"],"doi":["10.1093/jac/dkac127"]}}