biostudies-literatureTikiso TDepartment for International Development, UKEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentInfant Maternal Pediatric Adolescent AIDS Clinical Trials GroupNICHD NIH HHSNIAID NIH HHSACTGAdult Clinical Trial GroupNational Institutes of HealthIMPAACTNational Institute of Allergy and Infectious DiseasesFrench Development AgencyMedical Research CouncilNational Institute of Mental HealthTB AllianceWellcome TrustUBS Optimus Foundation1949-1959https://www.ebi.ac.uk/biostudies/studies/S-EPMC9633720biostudies-literatureUnknown77(7)<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.The Journal of antimicrobial chemotherapyPopulation pharmacokinetics of ethambutol in African children: a pooled analysis.PMC9633720UM1 AI106701R01HD069175MR/L004445/1AI068632UM1 AI068634UM1 AI068636R01 HD069175S003410206379/Z/17/ZU01 AI068632MC_UU_12023/26Tikiso TZar HJLee JAbdelwahab MTWiesner LAndrieux-Meyer IRabie HMcIlleron HCotton MFHesseling AChabala CDenti PDavies GBekker AfalsePopulation pharmacokinetics of ethambutol in African children: a pooled analysis.<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.2022-01-01T00:00:00Z2022 Jun2025-04-21T16:57:34.494Z2025-04-05T12:33:41.497ZS-EPMC96337203546637910.1093/jac/dkac127