At present, many medicines are not developed for children or available in suitable dosage regimen. Therefore, the FDA and the EMEA have launched initiatives that request pediatric assessment of new drugs. In recent years, the implementation of Physiologically based pharmacokinetic(PBPK) models in pediatric drug development has become more attractive and is widely used in both the USA and the European Union. The purpose of this research is to illustrate the development process involved in creation of a pediatric PBPK model incorporating existing adult drug data.
Sotalol and lorazepam were chosen as model drugs. In the process of modeling of PBPK from adult to child, the physicochemical data of the drug and anatomic/physiologic data for adult were obtained from literatures and used as input parameters, the initial PBPK model was produced with the compartments for gut, lung, brain, kidney, heart, muscle, adipose, and other tissues.
The evaluation of the initial PBPK for adult was done by comparing with experimental Pharmacokinetic(PK) profiles and the scaling from adult to pediatric was conducted using age-related changes in size such as tissue compartments, protein binding, and growth /maturation of elimination processes etc.
The PBPK model for pediatric was produced using the input parameters that were scaled and was evaluated for pediatric models. The experimental adult PK profiles of sotalol were 16 datas from 6 literatures. The experimental pediatric PK profiles of sotalol for eighty pediatric patients of different age groups with known age, gender, height, weight, dosing information, and measured plasma profiles were used from literature. As for lorazepam, 7 adult experimental PK profiles from 7 literature were used for the evaluations. and The experimental pediatric PK profiles of lorazepam were 2 datas from 2 literatures. The PBPK models evaluated in this study reflected properly the age-related pharmacokinetic changes and predicted adequately the sotalol and lorazepam exposure in children. The results obtained by sotalol were given an adequate description of sotalol pharmacokinetics in adults and in two years or more than pediatric age groups. In toddlers, infants, neonates, the mean ratio of observed data and predicted data for any PK parameter(AUClast, Cmax) exceeded a two-fold error range. The results obtained by lorazepam were given an adequate description of lorazepam pharmacokinetics in adults, but the mean ratio of observed data and predicted data for any PK parameter(AUClast, Cmax) in pediatrics exceeded a two-fold error range.
The PBPK models presented in this study have shown good predictability of observed data in adults and predicted adequately the sotalol exposure in children of different ages, except in children under the age of two. However, the lower predictabilities of the lorazepam PBPK model seen in pediatrics and the sotalol PBPK model seen in children under the age of two indicate the need for more pharmacokinetic studies. Therefore, more studies are needed to be done in pediatric drug development.