Knipp's 2nd Set Flashcards
Sites of Drug Metabolism
- First Pass Metabolism: GI, liver
- Systemic Metabolism: blood stream
Classes of Metabolism
Phase 1: metabolism of main compound
Ex. decarboxylases, oxygenase, deamidation
Phase 2: metabolism through addition, conjugation
Ex. glucuronidation, sulfation
Phase 3: transport - multidrug resistance
Objectives of Drug Metabolism
- eliminate the pharmacological activity of drug
- make a compound continuously more soluble until it cannot escape excretion
How to get Drug Metabolism
- change molecules shape to block its receptor binding
- change molecules lipophilic character to a more hydrophilic character & increase solubility
- increase molecules size
- make molecule more recognizable to efflux pumps
Metabolic Enzymes
- defense mechanism to highly lipophilic, aromatics that naturally occur in environment
Phase 1 Metabolism Focus
Cytochrome P450 –> CYP3A4
CYP3A5 actually metabolize many compounds thought to be done by CYP3A4
Process of Oral Absorption
- Drug molecule at surface dissolves to form saturated solution
- Dissolve drug pass throughout the dissolve fluid and diffuse from high to low concentration
- Drug molecules diffuse through bulk solution to mucosa
- Absorbed
Particle Size
- surface area increases as solids are broken into smaller pieces
- Increased SA leads to Increased Dissolution Rate
Dissolution
Rate of Dissolution
- dM/dt
- change in amount of mass of solution over time
Dependents of Dissolution
D: diffusion coefficient
S: surface area of tablet
h: thickness of layer
Cd: concentration of drug in donor
Ca: concentration of drug in bulk solution
Noyes Whitney Equation
dM/dt = DS/h (Cd-Ca)
- dissolution rate is proportional to D
- increase rate of diffusion –> increase dissolution
- dissolution rate is proportional to particle surface area
- dissolution rate is proportional to difference in concentration gradient
- high to low
- dissolution rate is inverse proportional to h
- increased h = less steep concentration gradient
- decrease h by increasing stirring rate
Permeability
- diffusion across a cell membrane barrier
Factors Limiting Oral Drug Absorption
Solubility
Dissolution
Permeability
Limited Solubility
Dissolution is fast
Permeability is Fast
Drug doesn’t get in solution
Observations:
- gut is saturated by high dose
- absorption does not increase with increased dose
Limited Dissolution
Tdiss is greater than residence time
Permeability is fast
Cant get out of dosage form
Observations:
- dissolution can be enhanced by particle size reduction
- absorption increases with increasing dose
Limited Permeability
Dissolution is fast
Permeability is low
Observations:
- amount of drug absorbed increases with increased dose
Rate Limiting Factors of Permeability
Physiochemical properties of drug
Physiochemical properties of membrane
Rate Limiting Factors of Dissolution
Physiochemical properties of drug
Physiochemical properties of formulation
Definition of Generic Drug
drug product that is comparable to brand in dosage form, strength, route of administration, quality and performance, and intended use
Therapeutic Equivalence
Pharmaceutical Equivalence
Bioequivalence
Pharmaceutical Equvalence
The same:
- API
- dosage form
- route of administration
- identical strength/concentration
Differ:
- shape, excipients, color
Bioequivalence
pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at same dose
a drug product is considered bioequivalent if 90% confidence interval of ratios of the test mean values for AUC and Cmax are within 80%-125%
Generic vs Brand Therapeutic Equivalence
- can contain the same AUC but not the same therapeutic effect
Study on Switch to Generic
2885 patients examined
- 70.5% no problems
- 10.8% including reappearance of problem
- 9.8% unspecified issue
- 8.8% other issues
30% of respondents reported an issue
IVIVC
- no correlation between bioavailability of generic vs brand
- no correlation between dissolution rate and AUC
ISSUE IN INTERCHANGEABILITY OF PRODUCTS
Mimicking Clinical Conditions
Dosage form design requires consideration of patient related variables
Patient related variables are not accurately assessed during development
Absorption windows are defined more based on physical-chemical properties and not physiology
Better in vitro and in vivo testing models are required for optimizing dosage form design
Control of Drug Performance
Interplay of excipients (formulation)
Physiochemical properties of drug
Physiological barriers between GI tract and site of action
Oral Delivery Summary
Oral formulations can control absorption rate to yield a safe and efficacious response
Dosage form design is dynamic and unpredictable so patient habits have to be considered
Patients vary in response
Generic formulations are not the innovator
Pharmacotherapy and Pregnancy
- 60 million women at reproductive age
- 10% are pregnant annually
- many are on meds for pre-existing conditions
- physiological changes alter ADME
- toxicity is concern
Fetal Imprinting
- genetics, diet, and environment can impact fetus
Linked to:
- cardivascular disease
- neurological disorder
- obesity and diaabetes
Pediatric Drug Development
- encourage pediatric drug development in order to create a situation where substantially more children have access to safe and effective medication
Challenges for Pediatric Testing
- lack of incentives for companies to study drugs on neonates, infant, children
- lack of technology to monitor patients and assay
- lack of suitable pediatric clinical infrastructure
Pediatric Pharmacology
- children are therapeutic orphans
- 20-30% of approved drugs have pediatric labeling
Why is it hard for pediatrics?
- children are not miniature adults
- dose on weight is not predictable
- animal studies are not predictive
- clinical studies fraught with ethical and financial hurdles
- administration of drug is hard
Pediatric Biopharmaceutics Classification System
- expedite generic and drug repurposing formulations
3 Factors the Influence Bioavailability
Solubility
Permeation
Dissolution
OATP1B1 SNP and Methotrexate Case Results
Low clearance rates are associated with higher toxicity
dose lowering and higher hydration must be required
Difference in Animals and Children
Length of gestation and timing of events
relative organ function maturity at birth
Overall Challenges in Pediatrics
Biological:
- ontogenic changes
- compositional changes
Clinical:
- clinical trials
- caregiver requirements
Formulation:
- dosage form selection
- flexibility in dosing
- excipient selection
- taste masking
Paradigm Shift
Going to protecting children from clinical research to protecting children through clinical research
Safety and Toxicology of Excipients for Pediatrics
- collaboration of EMA and NICHD
- draws attention to use of traditional excipients
- encourages greater use of solid dosage forms
Minitablet Formulation
Incorporation of BSC Class 1 and III
- less effect of formulation
Easy Translation to Market
- pediatric compliance
- flexible dosing
Minimal Excipients
- single filler, disintegrant, lubricant
Same Manufacturing Conditons
- size is constant
Film Advantage vs Disadvantage
Advantage:
- acceptable for patients with dysphagia
- easy and accurate
- increased stability
- faster onset of action
Disadvantage:
- difficult to manufacture
- moisture sensitivity
- limited dosing capacity
- increased packaging cost
What challenges Remain?
- age based dosage form
- children are not miniature adults
- animal models need to be refined
- better means of drug administration
