2017 - Budapest - Hungary

PAGE 2017: Drug/Disease modelling - Paediatrics
Alexios Tsiligiannis

Optimization of a paediatric FDC tablet and dosing regimen for the first line treatment of tuberculosis.

Alexios G. Tsiligiannis, Maria Sfouni and Aris Dokoumetzidis

Department of Pharmacy, National and Kapodistrian University of Athens, Greece

Objectives: This study was designed to optimize the strengths of a paediatric fixed dose combination (FDC) mini-tablet of isoniazid, rifampicin and pyrazinamide for the first -line treatment of tuberculosis, as well as the corresponding weight based dosing chart in the age range 0.5 to 8 years, using Modeling and Simulation.

Methods: Based on published population pharmacokinetic models (1) (2) (3), we simulated the exposures of Rifampicin, Isoniazid and Pyrazinamide in virtual adult South African patients, which are considered therapeutic. Doses were considered based on both, Rifater® SPC (a well-known and widely used adult anti tuberculosis product) and WHO guidelines for tuberculosis treatment. 970,200 scenarios of virtual paediatric Fixed Dose Combination tablets of first line anti tb drugs and weight bands were tested in silico on paediatric population, using Monte Carlo simulations carried out based on published PopPK models for children (4). The simulations were conducted in Matlab®R2016b. The dosing regimen which produced similar, according to a prespecified criterion, to adult exposures for all weight bands was chosen as the optimal one. 

Results: Simulations showed that the optimal dosing regimen includes a new FDC tablet with 90 mg of Rifampicin, 200mg of Pyrazinamide and 75mg of Isoniazid, administered as follows: 1 tablet for children with body weight ≥4 kg and <8kg, 2 tablets for children with body weight ≥8kg and <12 kg, 3 tablets for children with body weight ≥12kg and <18 kg and 4 tablets for children with body weight ≥18 kg and <28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages.

Conclusions: We optimized an anti-tuberculosis FDC tablet not based on predefined mg/kg doses but directly on therapeutic exposures similar to those of adults. This was done by a global optimization of the 3 strengths of the drugs and the weight cut-off points of the groups. A global optimization is needed because, although no synergy is considered between the drugs, all optimized parameters are correlated by the constraint that a single mini-tablet needs to be defined that its multiples scale well for the different age groups, such that the therapy is efficacious for all groups.

[1]Wilkins Justin J., Savic Radoika M., Karlsson Mats O. et al. Population Pharmacokinetics of Rifampin in Pulmonary Tuberculosis Patients, Including a Semimechanistic Model To Describe Variable Absorption. Journal of Antimicrobial agents and chemotherapy. 2008, Vol. 52, 6, pp. 2138–2148.
[2]Wilkins Justin J., Langdon Gran, McIlleron Helen et al. Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. European Journal of Clinical Pharmacology. 2006, Vol. 62, pp. 727–735.
[3]Wilkins Justin J., Langdon Grant, McIlleron Helen et al. Variability in the population pharmacokinetics of South African tuberculosis patients. British Journal of Clinical Pharmacology. 2011, Vol. 72, 1, pp. 51-62.
[4] Zvada SP., Denti P., Simonsson US. et al. Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses. Journal of Antimicrobial Chemotherapy. 2014, Vol.69, 5, pp.1339-1349

Reference: PAGE 26 (2017) Abstr 7178 [www.page-meeting.org/?abstract=7178]
Poster: Drug/Disease modelling - Paediatrics