Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling.

Xiaolu Han,Zengming Wang,Xiaoxuan Hong,Xianfu Li,Aiping Zheng,Yuxi Wang

doi:10.3390/children8110950

Abstract

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1–16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg−1 for ages 2–6 years and −0.0028 × Age + 0.1148 (mg/kg) for ages 7–16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

Highlights

With the changes in people’s dietary patterns and living habits in recent years, the incidence of essential hypertension in children is increasing year by year [1]
The AUC0-∞ (272.70 ng/h·mL) of the optimized PBPK model was close to the median of the clinical data (287.57 ng/h·mL), and the optimized model could be used for a PK simulation of amlodipine
The results showed all simulations in vivo; elimination of amlodipine be captured using the PBPK

Summary

Introduction

With the changes in people’s dietary patterns and living habits in recent years, the incidence of essential hypertension in children is increasing year by year [1]. According to the China Cardiovascular Disease Report, 3–4% of Chinese children had hypertension by the end of 2015, with an average annual growth rate of 0.47% [2]. Studies of pediatric drug safety data have shown that calcium channel blockers (CCBs) are the front-line medication for children with hypertension. Amlodipine is the only CCB approved by the FDA, since 2004, for the treatment of hypertension in children [3]. The clinical data on amlodipine in pediatrics are limited and focused on efficacy and safety [4,5,6]. In Europe and America, several studies have shown the pharmacokinetic differences of amlodipine between children and adults [7,8,9], while few studies have reported on its use in Chinese children

Methods

Results

Discussion

Conclusion