EXAM2 L3 Flashcards
Environmental Exposures Renaissance:
Infectious Agents
Fire Byproducts
Heavy Metals
Environmental Exposures today:
Infectious Agents
Fire Byproducts
Heavy Metals
Industrial chemicals
Chlorination byproducts
Vehicular Emissions
Pesticides
T/F: 66% of drugs have never been tested on pregnant women
True
Thalidomide Disaster
Was prescribed for morning sickness, caused significant increases in phocomelia, a birth defect consisting of no limns, or tiny flipper-like arms and legs, serious facial deformities, and defective organs
T/F: Exposure to xenobiotics are poorly understood
True
T/F: Xenobiotic target moves even further due to the environment
True
1962 Kefauver-Harris Drug Amendments did what?
Required efficacy and safety demonstration for FDA approval and marketing
Legislative incentives/mandates in place to promote pediatric development
FDA: Pediatric plan, BPCA, PREA
EU: Pediatric investigation plan (PIP)
WHO: Make medicines child size
Several practical challenges have discouraged the testing of drugs in pediatric populations including the lack of:
incentives for companies to study drugs in neonates, infants and children
Technology to monitor patients and assay very small amounts of blood
Suitable pediatric clinical infrastructure for drug trials
What percent of approved drugs have pediatric labeling
20-30%
Ways the FDA has encouraged pediatric studies
Financial incentive to conduct studies
Increased studies resulted in new labeling for 40 drugs
For approval of selective number of new drugs pediatric studies have been required
Developmental changes occurring from conception to adulthood is considered to be
Moving target
Why pediatric studies are difficult
Children are not mini adults
Animal studies not always predictive
Clinical studies in children fraught with ethical and financial hurdles
Admin. of drug can be probelmatic
BCS: Classification is based on what three factors that influences the drug’s bioavailability from a peroral formulation:
Solubility
Intestinal permeation acorss the intestinal barrier (in vitro vs in vivo)
Dissolution rate
T/F: There is an urgent need to expedite the development of pediatric formulations
True
PBCS stands for
Pediatric Biopharmaceutics Classification System
PBCS Class 1
(pediatric volume = 25ml): rapid dissolution (t50 = 15 min) for immediate release
PBCS Class 2:
(Subclasses a,b,c for acidic, basic and neutral drugs); Dissolution criteria are critically needed
BCS: Class 3:
Very rapid dissolution
BCS Class 4:
Same as BCS Class 2
T/F: Because Disposition drives safety and efficacy, there is a need for consideration of distribution , metabolism and elimination in the system-BDDCS
True
T/F: Low clearance rates are associated with higher toxicity
True; Dose lowering adjustments and higher hydration rates should be required in children carrying these phenotypes
What factors govern regulation of transporter expression and activity during growth and development?
Nuclear receptor regulation
Endocrine changes
Major Challenges in Studying Pediatric Drug Transporters
Limited availability of quality pediatric tissue (all age groups) 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 studies in children
Biological challenges with pediatrics:
Ontogenic changes
Compositional Changes
Clinical Challenges with pediatrics:
Clinical Trials
Caregiver Requirements
Formulation Challenges with pediatrics:
Dosage Form Selection
Flexibility in Dosing
Excipient Selection
Taste Masking
Differences between EMAs and FDAs view on pediatric trials
EMA will not allow a products release, including adult formulation, if their pediatric investigation Plan (PIP) isn’t satisfactory
Paradigm shift for industry
Changed from protecting children FROM research to protecting children THROUGH research
The safety and Toxicology of Excipients for Pediatrics Database
Collaboration between EMA and NICHD
Draws considerable attention to use of traditional excipients, particularly co-solvents for pediatrics vs. adults
Encouraging greater use of solid dosage forms
Factors important in mini-tablet platform formulation
Ability to incorporate BCS Class I and III
Easy translation to market formulation
Minimal Excipients
Same or Similar Manufacturing Conditions
Fractional Factorial DOE approach
Pharmaceutical Film Advantages
Acceptable for patients with dysphagia
Ease and accuracy of dosing
Increased stability compared to solutions/suspensions
Faster onset of action
Life cycle management
Pharmaceutical Film Disadvantages
Difficult to manufacture
Moisture sensitive
Limited dosing capacity
Increased packaging costs
Challenges that remain in pediatric pharmacology
Age based dosage form selection
Need for descriptive pharmacology in pediatric patients
Animal models need to be refined for prediction
Enable clinical studies in children by tackling ethical and financial hurdles
Better means of drug admin. are needed
