Review of Developmental Pharmacology

1
Review of Developmental Pharmacology
J. Steven Leeder, Pharm.D., Ph.D. Chief, Section
of Developmental Pharmacology Childrens Mercy
Hospital and Clinics Kansas City, MO
2
Goals of Presentation

• Review general principles related to drug
  metabolism throughout the developmental period
  spanning birth to adolescence
• Raise issues relevant to the extrapolation of
  adult doses to children at different
  ages/developmental stages

3
The Developmental Continuum

• Weight doubles by 5 months triples by 1 year
• Body surface area doubles by 1 year
• Caloric expenditure increases 3- to 4-fold by 1
  year
• Adolescence transition to adulthood
• Changes incomprehensible to most adults

?
4
Pharmacotherapy and the Developmental Continuum
5
What are the Key Developmental Issues Involved in
Determining

• Dose?
• Drug Clearance
• Acquisition of functional drug metabolizing
  enzyme and transporter activity
• Increases in activity during maturation
• Metabolite shunting
• Ontogeny of renal function
• Response?
• Ontogeny of drug targets and resistance
  mechanisms

6
Acquisition of Functional Drug Biotransformation
Activity

• Fetus essentially devoid of most drug metabolism
  activities
• CYP3A7 SULT
• Acquisition of postnatal functional activity
  isoform-specific with onset in
• Days (CYP2C9 CYP2D6)
• Weeks (CYP3A4)
• Months (CYP1A2)
• Activities peak in young children and decline to
  adult levels later (?puberty)

7
CYP3A7-CYP3A4 Switch
Lacroix et al. Eur J Biochem 247625, 1997
0.15
1.50
0.10
1.00
0.05
0.50
0.00
0.00
lt30 wk
gt30 wk
lt24 hr
1-7 d
8-28 d
1-3 mo
3-12 mo
gt1 yr
Adult
Fetus
Newborn
8
Phenytoin Elimination in Newborns
Bourgeois and Dodson, Neurology 33 173-8, 1983.
80
160
60
120
Phenytoin t50 (hr)
40
80
20
40
10
20
30
40
10
20
30
40
Initial Phenytoin Concentration (mg/L)
9
CYP1A2 Theophylline Metabolism
Kraus et al., Clin. Pharmacol. Ther. 54351-9,
1993.
10
Dextromethorphan Metabolic Pathway
11
Fractional Recovery of Major DM Metabolites
Fractional Recovery ()
DX
3HM
Postnatal Age (months)
12
Metabolite Shunting
13
Potential Consequences of Route Switching
Prodrug
Active Metabolite
Alternative Metabolite
14
Potential Consequences of Route Switching
When quantitative changes in primary metabolic
route occur, diversion of parent away from
expected metabolite formation may have clinical
consequences
15
Increased Clearance or Metabolic Activity
During Maturation
16
Distribution of Theophylline Dosage
RequirementsMilavetz et al. J. Pediatr. 109
351-4, 1986
75
75
Adult gt20 y.o. n49
Children 1-9 y.o. n337
50
50
Percentage of Patients
25
25
6
10
14
18
22
26
30
34
38
6
10
14
18
22
26
30
34
38
Dose (mg/kg/d)
17
Cyclosporine Dosing in Children and Adults
Jain et al. Trans. Proc. 232763-6, 1991.
Adults (42.313.4 yr)
Children (2.21.0 yr)
Mean Cyclosporine Dose (mg/kg/d)
41-52
33-40
25-32
21-24
17-20
13-16
9-12
7-8
5-6
4
3
2
1
Weeks Post Transplant
18
CYP3A4 Activity in Children Carbamazepine
Korinthenberg et al. Neuropediatrics 25 214-6,
1994
0.8
0.6
0.4
CBZ Epoxide/CBZ Ratio
0.2
0
0
100
200
50
150
Postnatal Age (weeks)
19
Normalized S-Warfarin Clearance
Takahashi et al., Clin Pharmacol Ther 68541,
2000
Prepubertal

Pubertal

Adult
20
Liver MassBody Weight Change with Age
Liver Mass ( Body Weight)
Age (years)
21
Normalized Antipyrine ClearanceMurry et al.,
Drug Metab Disp 231110, 1995
Antipyrine Clearance
p0.05
p0.01
mL/min/kg Body Weight
mL/min/L Liver Volume
22
Points to Ponder

• Increased clearance/dose requirements of some
  compounds in children may be a function of
  increased liver volumebody weight ratios
• May be most relevant when
• Biotransformation primarily hepatic
• Single enzyme quantitatively important
• May not necessarily apply to biotransformation by
  CYP3A4/5
• High enzyme content in intestinal mucosa and
  kidney

23
Summary

• Drug metabolism pathways acquired in
  isoform-specific patterns
• Ontogeny may show tissue specificity as well
• Activities appear to peak in young children and
  decline to adult levels later (?puberty)
• May be a function of increased liver massbody
  ratio or developmental gene regulation, or both
• Likely to be compound-specific issue
• Shunting a theoretical consequence of
  developmental changes in drug biotransformation

24
Acknowledgements

• Supported by Grant HD36783 from NICHD and Grant
  ES10855 from NIEHS
• NICHD PPRU sites at
• Childrens Mercy Hospital, Kansas City
• LSU Medical Center, Shreveport
• Arkansas Childrens Hospital, Little Rock
• LeBonheur Childrens Medical Center, Memphis
• Baylor University College of Medicine, Houston
• Childrens Hospital, Columbus