Population pharmacokinetics of child-friendly dispersible amoxicillin/clavulanate tablets in African children with severe community acquired pneumonia
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Background
Severe community-acquired pneumonia (CAP) remains a leading cause of mortality in children under five. The PediCAP trial evaluated oral step-down therapy using dispersible amoxicillin or amoxicillin/clavulanate tablets in African children hospitalised with severe CAP. Dispersible tablet formulations are preferred in children; however, pharmacokinetic data for oral amoxicillin/clavulanate in paediatric populations remain limited. We characterised the pharmacokinetics of 4:1, 7:1, and 14:1 dispersible amoxicillin/clavulanate tablets in children enrolled in the PediCAP trial and predicted target attainment under different dosing schemes.
Methods
Children were randomised within 24 hours of starting intravenous antibiotics to oral step-down therapy with weight-banded dosing of twice-daily amoxicillin/clavulanate (4:1, 7:1, or 14:1). Plasma concentrations were quantified following intensive sampling and analysed using nonlinear mixed-effects modelling with allometric scaling and postmenstrual age-dependent clearance maturation. Pharmacodynamic indices included %fT>MIC for amoxicillin and %fT>C t for clavulanate.
Results
A total of 157 children (median [range] age, 12 [2–70] months; weight, 8.4 [4.0-22.0] kg) contributed 707 paired concentrations. Amoxicillin was described by a two-compartment model and clavulanate by a one-compartment model, both with sequential zero-and first-order absorption. Typical clearance for an 8-kg individual at full maturation was 11.8L/h for amoxicillin and 6.1L/h for clavulanate. Pharmacokinetics were similar between the formulation ratios. Weight-banded dosing achieved balanced exposures across weight groups. Amoxicillin achieved 40%fT>MIC for MICs≤2mg/L. A proposed clavulanate target of 20%fT>0.5mg/L was achieved in most children even at the lowest amoxicillin/clavulanate ratio.
Conclusion
Weight-banded dosing using dispersible amoxicillin/clavulanate tablets provide consistent exposure profiles in African children with severe CAP.
SUMMARY
Population pharmacokinetic modelling of dispersible amoxicillin/clavulanate tablets (4:1, 7:1, 14:1) in 157 African children with severe pneumonia showed weight-banded dosing achieved consistent and adequate amoxicillin and clavulanate exposures across formulations.
