Population pharmacokinetics of ethambutol in African children: A pooled analysis

Objectives: 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. Methods: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25mg/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%). Results: 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 2months after birth and 99% by 3years. Typical steady-state apparent clearance in a 10kg child was 15.9L/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 3.16years or older. Conclusions: To obtain exposure within the 2-6mg/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.