Illustrative Example--Pediatrics: Challenges to Control Performance

Question 1

PK of drugs in pregnancy

Answer 1

-complex
-physiological changes alter ADME of drugs
-toxicity concern

Question 2

Fetal imprinting associated disease

Answer 2

-cardiovascular disease- Barker hypothesis
-neurological disorders
-obesity/diabetes

Question 3

Fetal imprinting

Answer 3

-affected by genetics, diet, environment etc
-very difficult to predict human effects (other factors, animal exposure studies)

Question 4

Drug therapy for pregnant women

Answer 4

-treatment for preggo rleads to treatment of baby which we do not wnat
-66% drugs have never been tested on preggos
-exposure to environmental xenobiotics

Question 5

Thalidomide disaster

Answer 5

-1950s sedative for morning sickness
-significantly increased phocomelia (no limbs, facial and organ deformaties)

Question 6

Endocrine disrupting chemicals (EDCs)

Answer 6

-ex diethylstilbesterol
-in utero programing of cancer in adolescent

Question 7

Xenobiotic exposure

Answer 7

can lead to changes in developmental PK/PD

Question 8

1962 Kefauver-Harris Drug Amendments

Answer 8

required efficacy and safety demonstration for FDA approval and marketing

Question 9

Legislature to promote pediatric drug development

Answer 9

FDA: pediatric plan, BPCA, PREA
EU: Pediatric investigation plan (PIP)
WHO: makes meds child sized

Question 10

Challenges to testing drugs on kids

Answer 10

-lack of incentive (them bitches not paying)
-technology to monitor little patients (L + not enough blood)
-pediatric clinical infrastructure for drug trials

Question 11

Pediatric approved drugs

Answer 11

-only 20-30% of drugs have pediatric labeling
-FDA encouragement (financial incentive, increased studies, requirement of new pediatric studies for drug approval)

Question 12

Pediatric Pharmacology challenges

Answer 12

-developmental changes
-organ development
-drug transporter and metabolizing enzyme otogeny

Question 13

Descriptive Pharmacology in pediatric patients

Answer 13

-lacking
-dosage based only on weight is not predicatble
-animal studies suck
-clinical studies upset the libs
-admin of drug also tbh

Question 14

PREA

Answer 14

-requires companies to assess use of new drugs in pediatric patients

Question 15

BPCA

Answer 15

financtial incentice for products studied in children

Question 16

Pediatrics Biopharmaceutics Classification System (PBCS)

Answer 16

-solubility
-permeability
-dissolution

Question 17

Class 1

Answer 17

rapid dissolution for immediate release

Question 18

Class 2

Answer 18

-subclasses (a,b,c) based on acidic, basic, or neutral drugs
-dissolution criteria critically needed

Question 19

BCS Class 3

Answer 19

very rapid dissolution

Question 20

BCS Class 4

Answer 20

same as BCS class 2

Question 21

Disposition

Answer 21

-drives safety and efficacy
-need consideration and distribution, metabolism, excretion

Question 22

OATP1B1 and metotrexate (MTX)

Answer 22

-genetic variations led to clearance differences
-low clearance = higher toxicity
-must lower dose and increase hydration rates in children with this phenotype

Question 23

What factors govern down regulation of transporter expression and activity during growth and development?

Answer 23

-nuclear receptor regulation
-endocrine changes

Question 24

Pediatric drug considerations

Answer 24

Do genetic variations add to age-related variation in drug transporter expression and function?

Impact of disease, drug-gene/food/drug interactions, and exposure to environmental chemicals on the expression and function of drug transport proteins

Question 25

Challenges in studying pediatric drug transporters

Answer 25

-limited availability of quality pediatric tissue for protein quantification and assessment of transporter function -lack of transporter specific probes to assess in vivo function -ethical and practical challenges with performing nontherapeutic stuies in children

Question 26

Challenges with pediatrics

Answer 26

-biological -clinical -formulation

Question 27

biological challenges

Answer 27

-ontogenic changes -compositional changes

Question 28

Clinical Challenges

Answer 28

-trials -caregiver requirements

Question 29

Formulation challenges

Answer 29

-dosage form selection -flexibility in dosing -excipient selection -taste masking

Question 30

EMA vs FDA

Answer 30

differing views on pediatric trials

Question 31

EMA

Answer 31

-will not allow a products release, including adult formulation, if PIP isnt satisfactory -encourages more pediatric formulations -could be ruining it for everyone else

Question 32

Paradigm shift

Answer 32

-protect children THROUGH research not FROM

Question 33

New challenges due to paradigm shift

Answer 33

-kids not mini adults -kids need to be age classified -require age appropriate formulations that used to be made through compounding -safety and efficacy models lacking

Question 34

Safety and Toxicology of Excipients for Pediatrics Database (STEP)

Answer 34

-collaboration between EMA and NICHD -draws attention to use of traditional excipients for kids vs adults -encouraging greater use of solid dosage forms

Question 35

Mini-tablet Platform formulation

Answer 35

-ability to incorporate BCS class 1 and 3 -easy translation to market formulation -minimal excipients -same or similar manufacturing conditions -fractional factorial DOE approach

Question 36

Ability to incorporate BCS class 1 and 3

Answer 36

-less effect of formulation -likely more beneficial for testing meds already on market

Question 37

Easy translation to market formulation

Answer 37

-pediatric compliance -flexible dosing -protected from degradation of vehicle or stomach

Question 38

minimal excipients

Answer 38

single filler, disintegrant, lubricant with functional coatings

Question 39

Similar manufacturing conditions

Answer 39

-size constant -number can fluctuate

Question 40

Fractional factorial DOE approach

Answer 40

-many process and formulation variables

Question 41

Advantages to Pharmaceutical film

Answer 41

-good for patients with dysphagia -ease and accuracy of dosing -increased stability -faster onset -life cycle management

Question 42

Disadvantages to Pharmaceutical film

Answer 42

-hard to make -moisture sensitive -limited dosing capacity -increased package costs

Question 43

Remaining Pediatric Challenges

Answer 43

-age based dosage form selection -need for descriptive pharmacology in pediatrics -animal studies need to be refined for prediction -enable clinical studies in children by removing ethical financial hurdles -better routes of administration needed