clinical pharmacology perspectives of pediatric dosing of over-the-counter (otc) cough and cold...

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


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


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


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



Summary


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)


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


Ontogeny of clearance mechanisms: Ontogeny of clearance mechanisms: Hepatic Clearance Hepatic Clearance

(Dextromethorphan as an example)(Dextromethorphan as an example)


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


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


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


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


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


Outline






Summary


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


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


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)



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



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


Outline





Pediatric drug development: FDA’s current thinking

Summary


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.


Outline Issues raised in citizen’s petition





Summary


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”


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


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)


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


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)


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


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


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?


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.


Back-Up Slides


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


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


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)

clinical pharmacology perspectives of pediatric dosing of over-the-counter (otc) cough and cold...

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