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 A.Strougo M. Danhof Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, NetherlandsA. B.Strougo (&) A. Yassen Global Clinical Pharmacology & Exploratory Development, Astellas Pharma Global Development Europe, Netherlands e-mail: C.T. Eissing S. Willmann Systems Biology & Computational Solutions, Bayer Technology, Germany D. Freijer Centre for Human Drug Research, Leiden, The Netherlands
Transcript
First dose in children physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development
Ashley Strougo bull Thomas Eissing bull Ashraf Yassen bull Stefan Willmann bull Meindert Danhof bull Jan Freijer
A Strougo 1113088 M Danhof Division of Pharmacology LeidenAmsterdam Center for Drug Research Leiden NetherlandsA
B Strougo (amp) 1113088 A Yassen Global Clinical Pharmacology amp Exploratory Development Astellas Pharma Global Development Europe Netherlands e-mail
C T Eissing 1113088 S Willmann Systems Biology amp Computational Solutions Bayer Technology Germany
D Freijer Centre for Human Drug Research Leiden The Netherlands
Introduction ndash key point
bull Guestimate for first dose in child usually scaled from adult values forndash PKndash PD
bull For PK generally either one of two approaches are usedndash Allometric Scaling +- maturationndash PBPK
Introduction cont
bull Allometric Scaling +- maturationndash Predict Volume of distribution and clearance using
power function derived from theoryndash Maturation function derived from existing PK data
bull PBPK models ndash Mathematical models taking into account
physiological factors such as blood flows organ volumes and partitioning between blood and organs s
Example Allometric Scaling
Example PBPK
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Introduction ndash key point
bull Guestimate for first dose in child usually scaled from adult values forndash PKndash PD
bull For PK generally either one of two approaches are usedndash Allometric Scaling +- maturationndash PBPK
Introduction cont
bull Allometric Scaling +- maturationndash Predict Volume of distribution and clearance using
power function derived from theoryndash Maturation function derived from existing PK data
bull PBPK models ndash Mathematical models taking into account
physiological factors such as blood flows organ volumes and partitioning between blood and organs s
Example Allometric Scaling
Example PBPK
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Introduction cont
bull Allometric Scaling +- maturationndash Predict Volume of distribution and clearance using
power function derived from theoryndash Maturation function derived from existing PK data
bull PBPK models ndash Mathematical models taking into account
physiological factors such as blood flows organ volumes and partitioning between blood and organs s
Example Allometric Scaling
Example PBPK
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Example Allometric Scaling
Example PBPK
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Example PBPK
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
AIM
bull Examine interchangeability of AS and PBPK
1 by using two drugs for which PK data in children is abundant -gt Paracetamol and Morphine
2 Hypothetical drugs
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods
bull Paracetamolndash Glucoronidation (UGT1A6) some sulfation
bull Morphinendash Glucoronidation (UGT2B7)
bull Substantial Differences in Extraction Ratio
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods ndash Para Morph
bull Using existing model simulate expected popPK in 29 age groups ndash (0 3 7 and 14 days 1 2 3 6 9 months 1 15
and 2 to 18 years in incremental steps of 1 year)ndash Dosing (Morph 10mg IV Paracetamol 1000mg)
bull Calculate AUC using NCA to get CLbull Compare individual quantiles with simulate
quantiles
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods Cont
bull PBPK clearance predictions compared with PK parameters from studies used to estimate MF
bull Compare AS Maturation functions with maturation function from PBPK
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods - Hypothetical drugs
bull Generate 108 hypothetical drugsndash Varying combinations of PK properties (see table 1)
bull PK route of elim lipophilicity blood flow protein binding
bull Use PBPK and AS to predict clearancendash 1mg dose IV infusion (30 mins)
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods - hypotheticals
bull Cl formula
bull AS formula
bull MF formula
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Methods
bull Relative prediction interval
bull Graphical Comparison
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
Results
First dose in children physiological insights into pharmacokin
Introduction ndash key point
Introduction cont
Example Allometric Scaling
Example PBPK
AIM
Methods
Methods ndash Para Morph
Methods Cont
Methods - Hypothetical drugs
Methods - hypotheticals
Methods
Results
Slide 14
Slide 15
Slide 16
Slide 17
First dose in children physiological insights into pharmacokin
