We aim to optimize the paediatric dosing regimen of isoniazid, rifampicin and pyrazinamide for the first-line treatment of tuberculosis, based on a fixed dose combination (FDC) mini-tablet using simulations. An optimization problem was set up to determine the 3 strengths of the drugs of the mini-tablet and 4 cutoff points that define the weight bands of a dosing chart, simultaneously. Using Monte Carlo simulations, first, exposure targets were determined for the 3 drugs, from published population pharmacokinetic models for adults, assuming that the approved doses for adults are de facto efficacious. Then optimal strengths and cutoff points were determined by matching children exposures generated from population pharmacokinetic models to the adults targets. The optimal dosing strengths of the FDC tablet were found to be 95 mg of rifampicin, 200 mg of pyrazinamide and 75 mg of isoniazid, and the 4 body weight bands for 1 to 4 mini-tablets, respectively were: 4 to 8 kg, 8 to 12 kg, 12 to 18 kg and 18 to 28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages. The higher doses proposed were evaluated to be much closer to the adult targets compared to the existing recommended by WHO paediatric doses.
Keywords: Fixed dose combination; Modelling and simulation; Paediatric posology; Tuberculosis.
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