Illustrative Example--Pediatrics: Challenges to Control Performance Flashcards
PK of drugs in pregnancy
-complex
-physiological changes alter ADME of drugs
-toxicity concern
Fetal imprinting associated disease
-cardiovascular disease- Barker hypothesis
-neurological disorders
-obesity/diabetes
Fetal imprinting
-affected by genetics, diet, environment etc
-very difficult to predict human effects (other factors, animal exposure studies)
Drug therapy for pregnant women
-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
Thalidomide disaster
-1950s sedative for morning sickness
-significantly increased phocomelia (no limbs, facial and organ deformaties)
Endocrine disrupting chemicals (EDCs)
-ex diethylstilbesterol
-in utero programing of cancer in adolescent
Xenobiotic exposure
can lead to changes in developmental PK/PD
1962 Kefauver-Harris Drug Amendments
required efficacy and safety demonstration for FDA approval and marketing
Legislature to promote pediatric drug development
FDA: pediatric plan, BPCA, PREA
EU: Pediatric investigation plan (PIP)
WHO: makes meds child sized
Challenges to testing drugs on kids
-lack of incentive (them bitches not paying)
-technology to monitor little patients (L + not enough blood)
-pediatric clinical infrastructure for drug trials
Pediatric approved drugs
-only 20-30% of drugs have pediatric labeling
-FDA encouragement (financial incentive, increased studies, requirement of new pediatric studies for drug approval)
Pediatric Pharmacology challenges
-developmental changes
-organ development
-drug transporter and metabolizing enzyme otogeny
Descriptive Pharmacology in pediatric patients
-lacking
-dosage based only on weight is not predicatble
-animal studies suck
-clinical studies upset the libs
-admin of drug also tbh
PREA
-requires companies to assess use of new drugs in pediatric patients
BPCA
financtial incentice for products studied in children
Pediatrics Biopharmaceutics Classification System (PBCS)
-solubility
-permeability
-dissolution
Class 1
rapid dissolution for immediate release
Class 2
-subclasses (a,b,c) based on acidic, basic, or neutral drugs
-dissolution criteria critically needed
BCS Class 3
very rapid dissolution
BCS Class 4
same as BCS class 2
Disposition
-drives safety and efficacy
-need consideration and distribution, metabolism, excretion
OATP1B1 and metotrexate (MTX)
-genetic variations led to clearance differences
-low clearance = higher toxicity
-must lower dose and increase hydration rates in children with this phenotype
What factors govern down regulation of transporter expression and activity during growth and development?
-nuclear receptor regulation
-endocrine changes
Pediatric drug considerations
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
Challenges in studying pediatric drug transporters
-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
Challenges with pediatrics
-biological
-clinical
-formulation
biological challenges
-ontogenic changes
-compositional changes
Clinical Challenges
-trials
-caregiver requirements
Formulation challenges
-dosage form selection
-flexibility in dosing
-excipient selection
-taste masking
EMA vs FDA
differing views on pediatric trials
EMA
-will not allow a products release, including adult formulation, if PIP isnt satisfactory
-encourages more pediatric formulations
-could be ruining it for everyone else
Paradigm shift
-protect children THROUGH research not FROM
New challenges due to paradigm shift
-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
Safety and Toxicology of Excipients for Pediatrics Database (STEP)
-collaboration between EMA and NICHD
-draws attention to use of traditional excipients for kids vs adults
-encouraging greater use of solid dosage forms
Mini-tablet Platform formulation
-ability to incorporate BCS class 1 and 3
-easy translation to market formulation
-minimal excipients
-same or similar manufacturing conditions
-fractional factorial DOE approach
Ability to incorporate BCS class 1 and 3
-less effect of formulation
-likely more beneficial for testing meds already on market
Easy translation to market formulation
-pediatric compliance
-flexible dosing
-protected from degradation of vehicle or stomach
minimal excipients
single filler, disintegrant, lubricant with functional coatings
Similar manufacturing conditions
-size constant
-number can fluctuate
Fractional factorial DOE approach
-many process and formulation variables
Advantages to Pharmaceutical film
-good for patients with dysphagia
-ease and accuracy of dosing
-increased stability
-faster onset
-life cycle management
Disadvantages to Pharmaceutical film
-hard to make
-moisture sensitive
-limited dosing capacity
-increased package costs
Remaining Pediatric Challenges
-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
