1. JOURNAL CLUB PRESENTATION First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development Ashley Strougo • Thomas Eissing • Ashraf Yassen • Stefan Willmann • Meindert Danhof • Jan Freijer
Strougo 􏰀 M. Danhof Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, NetherlandsA.
Strougo (&) 􏰀 A. Yassen Global Clinical Pharmacology & Exploratory Development, Astellas Pharma Global Development Europe, Netherlands
T. Eissing 􏰀 S. Willmann Systems Biology & Computational Solutions, Bayer Technology, Germany
Freijer Centre for Human Drug Research, Leiden, The Netherlands

2. Introduction – key points
Guestimate for first dose in child usually scaled from adult values for PK PD
For PK generally either one of two approaches are used
Allometric Scaling +/- maturation
PBPK
Dosing in Children in Complex, guessing the first dose for children in children is even tougher

3. Introduction cont Allometric Scaling +/- maturation PBPK models
Predict Volume of distribution and clearance using power function derived from theory
Maturation function derived from existing PK data
PBPK models
Mathematical models taking into account physiological factors such as blood flows, organ volumes and partitioning between blood and organs. s
Can also use empiric, ie guess without scientific back up….would you want that for you children. Allometric Scalling and PBPK models both have solid science behind them.

4. AIM Examine interchangeability of AS and PBPK
by using two drugs for which PK data in children is abundant -> Paracetamol and Morphine
Hypothetical drugs
Authors pick reasonal drug choices, giving hypothetical examples allow us to explore what if scenarios

5. Methods Paracetamol Morphine
Glucoronidation (UGT1A6), some sulfation
Morphine
Glucoronidation (UGT2B7)
Substantial Differences in Extraction Ratio
Including both high and low extraction ratio drugs is important, this article would be bias if not exploring both

6. Methods – Para, Morph
Using existing model simulate expected popPK in 29 age groups
(0, 3, 7 and 14 days; 1, 2, 3, 6, 9 months; 1, 1.5, and 2 to 18 years in incremental steps of 1 year)
Dosing (Morph 10mg IV, Paracetamol 1000mg)
Calculate AUC using NCA to get CL
Compare individual quantiles with simulate quantiles
Age groupings useful, frequent enough to pick up changes in the pk/pd relationshiop

7. Methods Cont
PBPK clearance predictions compared with PK parameters from studies used to estimate MF
Compare AS Maturation functions with maturation function from PBPK
Fair Comparision

8. Methods - Hypothetical drugs
Generate 108 hypothetical drugs
Varying combinations of PK properties (see table 1)
PK route of elim, lipophilicity, blood flow, protein binding
Use PBPK and AS to predict clearance
1mg dose, IV infusion (30 mins)

9. Methods - hypotheticals
Cl formula
AS formula
MF formula

10. Methods
Relative prediction interval
Graphical Comparison

11. Results
A few systematic over/underestimation errors can be seen for morphine in figure C

12. Systematic over/under estimation from previous slide still evident in figure C. Also not big difference in immature development of morphine figure 4

13. Maturation models highlight appreciable differences when choosing PBPK over allometric scalling