Elin M Svensson, Martin Näsström, Maria C Kjellsson, Mats O Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: To develop a model based methodology to guide design of FDCs and selection of an exposure based dosing regimen with the application to pediatric anti-tuberculosis (TB) drugs, individualized based on weight.
Methods: A rational approach for selection of optimal covariate-based dosing for single drugs has previously been developed [1]. Here, this methodology was expanded to accommodate several drugs simultaneously and a fixed tablet content. Further, the relationship between estimation stability and choice of equation mimicking the discontinuous step between dose-levels was investigated. Weights for children with a uniform distribution between 2-10 years were simulated based on the WHO growth standards [2] assuming log-normal distribution. Individual clearances for standard anti-TB drugs were simulated using published models [3-6] and allometric scaling. Estimation of optimal drug content per tablet and break points for change of dose were based on minimizing deviation between the logarithm of individual exposure (AUC) and a PK target, calculated from dosing recommendations.
Results: A function including exponentials with weight and break points as coefficients and a sigmoidicity factor was successfully used to mimic the step between dose-levels. However, using FOCE in NONMEM 7.2, estimation was unstable and dependent on initial estimates for high sigmoidicity factors. This could be overcome by sequential estimation of models with increasing steepness of the step function and successive update of initial estimates. The definition of optimization criteria should be carefully considered and depends on clinical considerations for the drugs. Optimization on overall target attainment can lead to systematic differences between groups. The benefit of increasing number of dose levels depends on the covariate relationship and the inter-individual variability (IIV) in the drug’s PK. For example, relative RMSE of the exposure decreased from 30 to 23% for pyrazinamide (low IIV) and 75 to 69% for rifampicin (high IIV), when changing from one to three dose levels.
Conclusions: An easy to employ and flexible methodology for design of FDCs was successfully developed. Anti-TB drugs were used as an example, but current results should not be interpreted as recommendations for FDC development. For such a proposal, the methodology should be applied with pediatric models, clinically valid targets and practical constraints such as co-formulation aspects.
Acknowledgement: The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution
References:
[1] S. Jönsson and M.O. Karlsson, Clinical Pharmacology and Therapeutics, vol. 73, 2003, pp. 7-13.
[2] WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: Methods and development. Geneva: World Health Organization, 2006.
[3] J.J. Wilkins et al, Antimicrobial Agents and Chemotherapy, vol. 52, 2008, pp. 2138-48.
[4] J.J. Wilkins et al, European Journal of Clinical Pharmacology, vol. 62, 2006, pp. 727-35.
[5] S. Jönsson et al, Antimicrobial Agents and Chemotherapy, vol. 55, 2011, pp. 4230-4237.
[6] J.J. Wilkins et al, British Journal of Clinical Pharmacology, vol. 72, 2011, pp. 51-62.
Reference: PAGE 22 () Abstr 2770 [www.page-meeting.org/?abstract=2770]
Poster: New Modelling Approaches