Prediction of Clearance in Children from Adults Following Drug–Drug Interaction Studies: Application of Age-Dependent Exponent Model

Abstract

Background and Objective Pharmacokinetic drug-drug interaction (DDI) studies are conducted in adult subjects during drug development but there are limited studies that have characterized pharmacokinetic DDI studies in children. The objective of this study was to evaluate if the DDI clearance values from adults can be allometrically extrapolated from adults to children. Methods Fifteen drugs were included in this study and the age of the children ranged from premature neonates to adolescents (30 observations across the age groups). The age-dependent exponent (ADE) model was used to predict the clearance of drugs in children from adults following DDI studies. Results The prediction error of drug clearances following DDIs in children ranged from 4 to 67%. Of 30 observations, 17 (57%) and 27 (90%) observations had a prediction error ≤ 30% and ≤ 50%, respectively. Conclusion This study indicates that it is possible to predict the clearance of drugs with reasonable accuracy in children from adults following DDI studies using an ADE model. The method is simple, robust, and reliable and can replace other complex empirical models.

A GFR-Based Method to Predict the Effect of Renal Impairment on the Exposure or Clearance of Renally Excreted Drugs: A Comparative Study Between a Simple GFR Method and a Physiologically Based Pharmacokinetic Model

“…Similarly, PBPK models are widely advocated for drug–drug interaction studies. In a recent study [ 33 ], Mahmood showed that the clearance of drugs following drug–drug interaction studies can be extrapolated to children from adult drug–drug interaction studies using a simple allometric model with reasonable accuracy.…”

“…It is also time that regulatory agencies worldwide recognize the uncertainty and inaccuracy of empirical models. New and simpler models should be acceptable in place of traditionally complex models as adding complexity to a model does not necessarily improve the predictive power of a model [ 23 – 33 ]. The new and simpler models will be cost and time effective (as shown in this study and some previously published studies [ 26 – 33 ]) and attention should be focused on their development.…”

“…New and simpler models should be acceptable in place of traditionally complex models as adding complexity to a model does not necessarily improve the predictive power of a model [ 23 – 33 ]. The new and simpler models will be cost and time effective (as shown in this study and some previously published studies [ 26 – 33 ]) and attention should be focused on their development. A minimal physiological model is a good step in this direction and considering the overall predictive performance of the minimal physiological model, the use of a whole-body physiological model is questionable.…”

Medications Administrated to Children

“…Stejně jako dospělí, jsou i děti vystaveny interakcí mezi jednotlivými léčivy, která může vést ke změně koncentrace léčiv. Tento proces může být způsoben změnou absorpce, distribuce, metabolismu a eliminace (Mahmood, 2020).…”

“…Z těchto důvodů se staly studie nedílnou součástí nynějšího vývoje léků a lékové terapie. Autor (Mahmood, 2020) ve své studii poukazuje na lékové interakce, které se mohou vyskytnout u pediatrických pacientů stejně jako u dospělých a také zde upozorňuje na problém, který souvisí s interakcí nejen mezi dvěma podávanými léky, ale také interakci mezi potravinou a lékem a u dospívajících pubescentů upozorňuje na interakci mezi lékem a drogou, alkoholem, kouřením. Farmakodynamická interakce může vést k aditivním, synergickým nebo antagonistickým účinkům léčiva.…”