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Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18-19, Citizen Petition - Raised significant concerns about the safety and efficacy of cough and cold medications in children 6 years and younger - Requested FDA to re-label these products to state that these products should not be used for the treatment of cough and cold in children under 6 years of age - Raised significant concerns about the safety and efficacy of cough and cold medications in children 6 years and younger - Requested FDA to re-label these products to state that these products should not be used for the treatment of cough and cold in children under 6 years of age
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Clinical Pharmacology Perspectives of Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications(OTC) Cough and Cold Medications
Joint Meeting of the Nonprescription Drugs Advisory Committee Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeeand the Pediatric Advisory CommitteeSilver Spring, MarylandSilver Spring, MarylandOctober 18-19, 2007October 18-19, 2007
Partha Roy, Ph.D. Partha Roy, Ph.D. Senior Clinical PharmacologistSenior Clinical PharmacologistOffice of Clinical PharmacologyOffice of Clinical PharmacologyOffice of Translational SciencesOffice of Translational Sciences
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Outline
Issues raised in citizens petition
Ontogeny of renal and hepatic (metabolic) clearance mechanisms with age
Available pediatric PK data for OTC cough and cold drugs
Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution
Pediatric drug development: FDA’s current approach
Summary
3Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Citizen Petition
- Raised significant concerns about the safety and efficacy of cough and cold medications in children 6 years and younger
- Requested FDA to re-label these products to state that these products should not be used for the treatment of cough and cold in children under 6 years of age
4Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Basis for the petition
Reports of deaths and serious adverse events in which drugs commonly found in OTC cough and cold preparations were detected at very high concentrations mostly in infants and toddlers
The absence of specific dose and dosing interval information on the label for children under the age of 2 years constitutes a safety hazard in an age range highly vulnerable to overdose
5Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Outline
Issues raised in citizen’s petition
Ontogeny of renal and hepatic (metabolic pathways) functions with age
Available PK data for OTC cough and cold drugs
Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution
Pediatric drug development: FDA’s current approach
Summary
6Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Clearance pathwaysClearance pathways
Drugs ClassClearance
Renal Metabolic
Pseudoephedrine Decongestant Major (55-75%) Minor
Guaifenesin Expectorant Minor Major (unknown CYPs)
Dextromethorphan Anti-tussive Minor Major (CYPs 2D6, 3A4, 2B6)
Chlorpheniramine Anti-histamine Minor Major (CYPs 2D6 & 2C19)
Brompheniramine Anti-histamine Minor Major (unknown CYPs)
Diphenhydramine Anti-histamine Minor Major (CYPs 2D6, 1A2, 2C9 & 2C19)
7Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Ontogeny of clearance mechanisms: Ontogeny of clearance mechanisms: Renal Clearance (e.g. Pseudoephedrine)Renal Clearance (e.g. Pseudoephedrine)
Hayton WL (2002) AAPS PharmSci 2 (1) article 3 (http://www.aapspharmsci.org)
Renal maturation complete by 2 years of life
Glomerular Filtration
Active Secretion
Renal Blood flowRFP: Renal Function Parameter
2 years
8Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Ontogeny of clearance mechanisms: Ontogeny of clearance mechanisms: Hepatic Clearance Hepatic Clearance
(Dextromethorphan as an example)(Dextromethorphan as an example)
9Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Impact of CYP2D6 polymorphism on Impact of CYP2D6 polymorphism on drug exposure: Dextromethorphandrug exposure: Dextromethorphan
Adopted from Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516
CYP2D6EM
CYP2D6PM*
Cmax (ng/mL)
2.4(0.5 – 5.9)
207(182 – 231)
T1/2
(hr)3.4 24
* 5-10% of Caucasians, 1-3% of Asians
EM: extensive metabolizersPM: poor metabolizers
Dextromethorphan (DM) PK in adults
10Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Ontogeny of CYP2D6 in the 1Ontogeny of CYP2D6 in the 1stst year of life: year of life: Dextromethorphan (DM) / Dextrorphan (DX) urinary ratio as probeDextromethorphan (DM) / Dextrorphan (DX) urinary ratio as probe
Adopted from Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516
No apparent age-related differences in CYP2D6 activity from 2 wks to 1 y of age
Large inter-individual variability ~ CYP2D6 genetic polymorphism
11Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Ontogeny of CYP3A4: Midazolam as a probeOntogeny of CYP3A4: Midazolam as a probe
de Wilt et al. (1999) Clin. Pharmacokinet 37: 485-505
CYP3A4: gradual increase after birth acquiring 3/4th of adult activity by 2 y
Midazolam clearance in 2-15y > adults
12Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Ontogeny of other CYPs: 1A, 2B6, 2C, 2D6, 3A5, 2E1
Ontogeny of Phase II enzymes (e.g. UGT)
Ontogeny of drug transporters
Effect of diet (breast feeding vs. formula feeding) on
the ontogeny of drug metabolizing enzymes
Effect of pH: Gastric (absorption) and urinary
(elimination)
Additional factors impacting drug exposure:Additional factors impacting drug exposure:Limited to lack of informationLimited to lack of information
13Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Summary of development of clearance pathways
Renal:
Renal maturation complete by 2 years
Metabolic:
Each drug metabolizing enzymes (DMEs) demonstrate an independent rate and pattern of maturation
Genetic polymorphism of DMEs impacts drug exposure in children
Large inter-individual variability in metabolic clearance in children
14Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Outline
Issues raised in citizen’s petition
Ontogeny of renal and hepatic (metabolic pathways) functions with age
Available PK data for OTC cough and cold drugs
Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution
Pediatric drug development: FDA’s current approach
Summary
15Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
OTC Monograph Dosing in Children:OTC Monograph Dosing in Children:Current PracticeCurrent Practice
Extrapolated from dosing in adultsWide margin of safetyBased on age: convenientStratification mimics body weight
Age ≥ 12 y 6 – 11 y 2 – 5 y < 2 y
Mean weight (kg) 60 31 17 7.5 – 12.5*
Monograph Dose:Decongestant,
Expectorant, Antitussive
adult dose
1/2 ofadult dose
1/4 ofadult dose
Consult a doctor
Antihistamine adult dose
1/2 ofadult dose
Consult a doctor**
Consult a doctor
* Range ** Professional labeling available
16Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
PK parameters Pediatrics (<2y)
Pediatrics (2-5y)(rhinitis patients)
N = 7
Pediatrics (6-11y)(healthy)
N = 28
Adults (18-44y)(healthy)
N = 25
Dose (mg) _ 15 30 60
AUC (ng.hr/mL) _ 1292 (41) 1735 (27) 2424 (26)
Cmax (ng/mL) _ 179 (17) 218 (24) 254 (21)
Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-373 (Children’s Advil Cold Suspension) and NDA 21-374 (Advil Cold Sinus Liquigels)
Mean (CV%) Pseudoephedrine single dose Mean (CV%) Pseudoephedrine single dose PK in adults and childrenPK in adults and children(Cross-study comparisons)(Cross-study comparisons)
- Systemic exposure in 2-11y children NMT adults- No PK data in children less than 2 years of age
17Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Mean (CV%) Chlorpheniramine single dose Mean (CV%) Chlorpheniramine single dose PK in adults and childrenPK in adults and children(Cross-study comparisons)(Cross-study comparisons)
PK parameters Pediatrics (<6y)Pediatrics (6-11y)(rhinitis patients)
N = 30
Adults (18-44y)(healthy)
N = 29
Dose (mg) _ 2 4
AUC (ng.hr/mL) _ 131 (52) 194 (76)
Cmax (ng/mL) _ 7.3 (4.4) 8 (1.3)
Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-587 (Children’s Advil Allergy Sinus Suspension)
- Systemic exposure in 6-11y children NMT adults- No PK data in children less than 6 years of age
18Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Mean Brompheniramine single dose PK in Mean Brompheniramine single dose PK in adults and childrenadults and children
(Cross-study comparisons)(Cross-study comparisons)
PK parameters Pediatrics (<6y) Pediatrics (6–11y)N = 14
AdultsN = 7
Dose (mg/kg) _ 1.3 1.3
AUC (ng.hr/mL) _ 127 293
Cmax (ng/mL) _ 7.7 11.6
Adopted from Simons et al. (1999) J Allergy Clin. Immunol. 103: 223-26
- Systemic exposure in 6-11y children NMT adults- No PK data in children less than 6 years of age
19Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Focus on Clearance (CL/F)Focus on Clearance (CL/F)
Cross-study comparisons
0
0.2
0.4
0.6
0.8
1
1.2
1.4
PSE CHLOR BROM
OTC Drugs
Ora
l Cle
aran
ce (L
/h/k
g)
Adult6 - 11 y2 - 5 y
20Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Outline
Issues raised in citizen’s petition
Ontogeny of renal and hepatic (metabolic pathways) functions with age
Available PK data for OTC cough and cold drugs
Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution
Pediatric drug development: FDA’s current thinking
Summary
21Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
C:P ratio (measure of post-mortem redistribution) C:P ratio (measure of post-mortem redistribution) for OTC cough and cold drugsfor OTC cough and cold drugs
site & timing of post-mortem blood collection
type of biological matrix
sample processing
physicochemical characteristics of the drug: pka, volume of distribution
Drugs C:P ratio*
Chlorpheniramine 3.1
Dextromethorphan 2.0
Diphenhydramine 2.3
Pseudoephedrine 1.5
* C:P ratio = heart blood : peripheral blood ratio
Factors influencing post-mortem drug redistribution
Reference: Leikin JB and Watson WA. (2003) Clinical Toxicology, 41, 47-56.
22Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Outline Issues raised in citizen’s petition
Ontogeny of renal and hepatic (metabolic pathways) functions with age
Available PK data for OTC cough and cold drugs
Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution
Pediatric drug development: FDA’s current approach
Summary
23Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
FDA’s Current Approach:FDA’s Current Approach:Objectives of Pediatric PK studies
Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population states the following:
…..“Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendation”
Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products states the following:
….. “In general, pharmacokinetic studies in the pediatric population should determine how the dosage regimen in the pediatric population should be adjusted to achieve approximately the same level of systemic exposure that is safe and effective in adults”
24Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
FDA’s Current ApproachFDA’s Current ApproachBridging efficacy data in an adult population to a Bridging efficacy data in an adult population to a
pediatric populationpediatric population
Reference: FDA’s Guidance for Industry (2003), Exposure-Response Relationships — StudyDesign, Data Analysis, and Regulatory Applications
25Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Key Considerations for Pediatric PK studies
Monotherapy: single ingredient evaluation
Single and multiple dose evaluation
Adequate number of subjects within each age group
Range of doses within each age group
Sparse sampling for population PK approach
Adequate collection of covariate data (age, BW, gender)
26Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Lessons learned from FDA’s decade-long pediatric initiatives
Outcome of well-designed pediatric PK/Safety studies:
Critical labeling changes that include unique pediatric dosing
Focus on drug clearance and its variability in children
Pediatric dosing not always obtained by simply applying BW or
BSA based calculations to the adult dose
Systemic exposure in children not always predictable based on
prior adult information
27Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Dose prediction from Population PK analysis (NDA 21563)
Optimizing Pediatric Dosing: Optimizing Pediatric Dosing: Desloratadine (ClarinexDesloratadine (Clarinex®®) as an Example) as an Example
Age Group Cmax AUC Dose q.d. (mg)
Adults 2.3 (51) 48.4 (54) 5
6-11y 2.23 (35) 55.5 (100) 2.5
2-5y 2.68 (50) 45.1 (56) 1.25
Age Group CL/F (L/hr) Predicted* pediatric q.d. dose (mg)
Adults 137 (58) 5
1-2y 35.5 (51) 1.29 (0.63-1.96)
½-1y 27.8 (35) 1.01 (0.66-1.37)
*CLpredicted / CLadult x adult dose
Dose determination from traditional PK analysis (NDA 21300)
28Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Dosing Recommendations:Dosing Recommendations:Adults and children ≥12 years: 5 mg once daily
Children 6 to 11 years of age: 2.5 mg once daily
Children 12 months to 5 years of age: 1.25 mg once daily
Children 6 to 11 months of age: 1.0 mg once daily
Optimizing Pediatric Dosing: Optimizing Pediatric Dosing: Desloratadine (ClarinexDesloratadine (Clarinex®®) as an Example) as an Example
29Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Summary (1)
No pediatric PK data for a large number of OTC cough
and cold drugs
Based on the data we have, PSE, CHLOR and BROM
monograph doses DO NOT appear to exhibit greater drug
exposure in children relative to adults
As in adults, drug clearance is highly variable in children
and not readily predictable based on prior adult
information
30Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Summary (2)
Factors impacting clearance mechanisms in children: ontogeny genetic polymorphism
Post-mortem drug redistribution may partly explain high Post-mortem drug redistribution may partly explain high
post-mortem levels in reported casespost-mortem levels in reported cases
To optimize pediatric dosing of OTC cough and cold To optimize pediatric dosing of OTC cough and cold
drugs: should additional PK studies be conducted and if drugs: should additional PK studies be conducted and if
so, for which ingredients and what ages? so, for which ingredients and what ages?
31Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
AcknowledgementsAcknowledgements Office of Clinical Pharmacology /
Division of Clinical Pharmacology II– Emmanuel (Tayo) Fadiran, Ph.D.– Wei Qiu, Ph.D.– Suresh Doddapaneni, Ph.D.– Chandrahas Sahajwalla, Ph.D. – Sally Choe, Ph.D.– Abimbola Adebowale Ph.D.
32Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Back-Up Slides
33Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Example of Optimal Pediatric Dosing (1) Example of Optimal Pediatric Dosing (1) ZosynZosyn®®: Application of Pop PK Analysis: Application of Pop PK Analysis
Adopted from Tornoe et al. (2007) Int. J. Antimicrob. Agents, 30, 320–324.
Zosyn® is Piperacillin (PIP) /Tazobactam (TAZ), an IV antibacterial combination product
Eliminated via kidney
Comparable adult exposure as a basis for optimizing pediatric dosing
Pediatric dosing incorporated clearance maturation rate below the age of 9 months
Data from 2 pediatric PK/safety studies
34Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Adopted from Tornoe et al. (2007) Int. J. Antimicrob. Agents, 30, 320–324.
Dosing recommendation:Dosing recommendation: Adults and children weighing >40 kg: 3.375 g every six hours totaling 13.5 g (12.0g PIP / 1.5g TAZ) per day.
Children ≥ 9 months up to 40 kg: 100 mg PIP / 12.5 mg TAZ per kg, q 8h
Children 2 to < 9 months: 80 mg PIP / 10 mg TAZ per kg, q 8h
Example of Optimal Pediatric Dosing (2) Example of Optimal Pediatric Dosing (2) ZosynZosyn®®: Application of Pop PK Analysis: Application of Pop PK Analysis
35Joint Meeting of the Nonprescription Drugs Advisory Committee and Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committeethe Pediatric Advisory CommitteeOctober 18-19, 2007October 18-19, 2007
Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516
Metabolic shift from DX (CYP2D6 metabolite) to 3HM (CYP 3A4 metabolite)
Ontogeny of CYP3A4 in the 1Ontogeny of CYP3A4 in the 1stst year of life: year of life: Fractional urinary recovery of 3-hydroxymorphinan (3HM)Fractional urinary recovery of 3-hydroxymorphinan (3HM)