Exam 3 Flashcards
Partition Coefficient
Ratio of concentrations in two immiscible solvents (eg octanol and water); K(o/w)=COctanol/CWater
pH-partition hypothesis
For drugs absorbed by a passive, transcellular mechanism; permeability transport depends on the fraction of unionized drug at the intestinal pH
Solubility and partition coefficient
in general as ko/w increases, solubility decreases
Solubility depends on
- molecular structure
- physical state (solid, liquid)
- composition of solvents (types, co-solvent perentages, solution components, pH/temperature)
- measurement methods (equilibration time, detection method)
Physicochemical properties of the drug that affects absoprtion
- solubility
- drug stability in solution
- lipophilicity
- molecular size and shape
- pka of the ionizable groups
- physical state of the drug (amorphous vs. crystalline, polymorphism, hydrates/solvates,liquid/gaseous)
***Factors governing drug performance in the clinic
- physicochemical properties of the API
- physicochemical properties and the composition of the formulation
- physiological barriers that influence the “targeted bioavailability” of the drug
Performance
- the ability of the drug to elicit a therapeutic response
- the ability of the drug to stay in a safe therapeutic range during the dosing regimens
- a lack of a toxic or non-efficacious response
- described by both pharmacokinetics and pharmacodynamic processes
- it is a function of the drug, the formulation and the body - it can be a moving target
Druggable protein
proteins that can bind drug-like compounds with binding affinity below 10mM (it is inferred that the compound must be able to functionally modulate the protein)
Gene
druggable genees are identified by pharmacogenomic methods
protein
genes that encode disease-related proteins that can be modulated by drug-like molecules are identified
pharmacophore
druggable genes are converted to proteins using in silico methods and binding cavities can be identified
Druggability Stages
- discovery stage
- assesses the ability of NCEs to bind to the drug target
- in this stage, in vivo models are used to assess
Developability
- refers drug product performance
- incorporates factors like biorelevant solubility and dissolution
- formulation factors releated to ADME/T incorporated
Overcoming the effects of the pH Partition Hypothesis
- functionalize the compound-change pKa
- prodrug strategy (modify the charged moiety, modify the molecule to be recognized by a transporter)
- salt selection (ion pairing effective in improving permeation, salt form can alter unionized fraction)
- drug delivery system
Formulation design requires a consideration of:
- Physicochemical properties of the drug
- physicochemical properties and composition of the formulation
- biological factors that influence performance (ADME and toxicity; ADMET)
Formulation design requires a consideration of:
- Physicochemical properties of the drug
- physicochemical properties and composition of the formulation
- biological factors that influence performance (ADME and toxicity; ADMET)
Formulation Factors Affecting Absorption
- Dosage Form design (size, excipient compositions, etc/manufacturing parameters brief discussion)
- Rates of drug release from the dosage form (disintegration, dissolution, deaggregation, erosion of coatings, osmotic pumps)
- Residence time at absorption site (mucoadhesives, coatings)
What are excipients?
- usually inert substance that forms a vehicle
- substances added to therapeutically active compounds to improve appearance, bioavailability, stability, and palatability of the product
Excipients…
- are not inert
- US warning on HIV excipient
- Glaxo Wellcome’s protease inhibitor (Agenerase) is warned to be dangerous due to the amount of propylene glycol in solution
13 Functional classes (IPEC - America)
- Binders
- Disintegrants
- Fillers (Diluents)
- Lubricants
- Glidants (flow enhancers)
- Compression aids
- Colors
- Sweeteners
- Preservatives
- Dispersing Agents
- Film formers
- Flavors
- Printing Inks
Common Excipients
- Cellulose based (microcrystalline cellulose)
- sugars (sucrose, lactose, mannitol)
- Starch
- synthetic polymers
- Inorganic
- Magnesium stearate
Critical Factors
- origin, source and availability
- functional catergory
- quality and purity
- impurity levels and extent of characterization
- batch-to-batch consistency
- stability in the pure form and in formulation
- compatibility with active and packaging material
- toxicological considerations
- cost, regulatory or compendial status
- biological activity, if any
- patent status
Common Methods for Excipient Compatability Testing
- Binary or formulation blends
- Binary or formulation blends with 10 - 20% w/w water
- Suspension or solution of excipients and drug
- Mechanical stress by milling or co-milling drug
- Using amorphous drug
- Compacts of prototype formulation by direct compression
- Tablets processed by wet granulation
- Calorimetry
Flow Properties - Angle of Repose
- excipients can be used to control flow-glidants
- better flow means better mixing and filling
- increases ability to keep dose the same
- the angle of repose is a characteristic of how well a powder flows
- SMALLER ANGLE = INCREASED FLOW
Organoleptic Senses to consider when coating/binding (clinical trials) treatments
- sight (size, color, shape, markings)
- smell
- sound (tablet/pellet inside a capsule)
- taste
- touch
Those affecting bioavailability, stability, and marketing considerations
- disintegrants-enhance rate of disintegration/dissolution
- coatings-control release
- flavors/sweeteners-mark drug taste
- colors-recognition
- miscellaneous ingredients
Physiological Factors Affecting Absorption
- absorbing surface area
- residence time at absorption site
- pH changes in lumen
- permeability/perfusion (functional and molecular characteristics of transporter and metabolism)
- dietary fluctuations/effects
- complexation/protein binding
- biliary uptake and clearance
Epithelia
- predominantly used for external surfaces although endothelial cells are epitheliod (sit on a layer of extracellular matrix proteins; epithelial cells are polarized with directional transport)
- there are several different types
- endothelial cells line the inside surfaces of body cavities, blood vessels and lymph - they have simple squamous morphology. Endo = in, therefpre internal surfaces
Simple squamous types
- thin layer of flattened cells that are relatively permeable
- lines most blood vessels
- placenta, endothelial cells (?)
Simple columnar types
usually found in the GI tract
Translational types
comprised of several layers with different shapes - usually required to stretch
Stratified squamous types
multiple layers of squamous cells that cover areas subject to wear and tear - skin is one type that the barrier function comes from keratinization
Composition of biological membranes
- all living cells are enclosed by one or more membranes, which define the cell as the living unit
- the membrane isolates the cellular contents from the environment - forms a barrier
- the cell membrane is a semi-permeable membrane, permitting the rapid passage of some chemicals while retarding or preventing the passage of others
- cellular lipid composition is polarized and intracellular membrane lipids are different than extracellular lipids
Does cholesterol only have harmful effect on membranes
No, it provides fluidity at lower levels. Actually, when it exceeds a certain level in a membrane, the membrane undergoes a phase transition and forms a liquid crystalline state.
We call this hardening atherosclerosis when it occurs in the vasculature.
Tight Junctions
- important for the function of the confluent epi-/endothelia
- restrict solute movement between the cells (paracellular)
- polarize cells into apical (luminal - blood facing) and basolateral (abluminal - brain facing) areas
- allow for differing functions between the two membranes
- TJs can involve up to 50 proteins
Cell-Based Assays
Look up equations.
Intestinal Transport Mechanisms
- Passive (non-saturable)
- **paracellular (between cells)
- **Transcellular (through cells)
- Carrier-Mediated (saturable)
- **active (energy dependent)
- **facilitated diffusion (energy independent)
General Interpretation of Caco-2 vs. PAMPA Data
See chart.
Drug transporters
Drug transporters are membrane-bound proteins widely distributed throughout the body, prominently on apical and basolateral surfaces of organs involved in clearance
Physiological role of these transporters is to move important molecules across membranes; this capacity includes moving drug molecules across membranes
Drug transporters are a crucial determinant of tissue and cellular distribution of drugs, not only for drug clearance but also sanctuary organs
Variations in drug transporter activity can be major determinants of drug response and drug safety
This has primarily been identified in adults with much less data in children
Solute Carrier (SLC)
43 Subfamilies
> 300 members identified
Generally influx or secretory efflux transporters
PepT1, OATs, OATPs
ATP-Binding Cassette (ABC)
7 Subfamilies
50 members presently identified
Generally efflux- multidrug resistant transporters
P-glycoprotein, MRPs
Absorption
Refer to diagram.
Conventional Terminology: Influx Transporters
Transfer substrates into cells
Conventional Terminology: Efflux Transporters
pump substrates out of cells
Conventional Terminology: Absorptive Transporters
Transfers substrates into the systemic blood circulation
Conventional Terminology: Secretory Transporters
transfer their substrates from the blood circulation into bile, urine, and/or GI lumen
Passive Paracellular Permeation
Hydrophilicity.
Molecular Size and Shape
pKa of the ionizable groups
Linear increase in permeability with increasing concentration
Adjuvants can open tight junctions and increase
transport
Facilitated/Active Transcellular Permeation
Affinity (Km), Capacity (Vmax/Jmax)
Concentration dependent saturation
Expression level (constitutive, induced).
Function (drug-drug & drug-nutrient interactions, competitive inhibition.)
Excipients like surfactants can limit the effects of efflux by Pgp or BCRP.
Variability in Cell Based Assays
The FDA is now paying significant attention to cell based permeability assay variation.
Affinity for multiple transporters can obfuscate physiologically relevant predictions
Inherent variability leads to differences in PAPP values for the same drug
Divided into three categories
Cell Culture Methods/Techniques
Transport Experiments
Data Analysis
GI Tract Epithelia
Oral Cavity-Buccal (stratified squamous epithelium) and Sublingual (simple squamous epithelium)
Esophagus is comprised of a stratified squamous epithelium, with the trachea being comprised of psuedostratified squamous epithelial cells.
Stomach is comprised of predominantly columnar epithelial cells, mixed with other cell types like mucus producing goblet cells, and parietal (acid secreting) and enterochromaffin-like (histamine secreting) cells.
The Small and Large Intestines are also lined with predominantly columnar epithelial cells. These cells are mixed with many different cell types.
Rectum has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near the anal sphincter) half.
The Role of the Stomach
To digest food and control the flow of its contents into the intestine.
- Acts as a food reservoir
- Processes food into fluid chyme for nutrient absorption
- Regulates food delivery to intestine
- pH protects against most bacteria, allows pepsin to function
Fasted pH in normal, healthy adults < 3
Fed pH is in the range of 5 to 7.
Gastric emptying half-time is about 30 min.
Fasted emptying cycles through 4 phases culminating with a “Housekeeper” Wave.
Fed state, no defined cycle.
Organization of the Stomach
Three primary regions:
- Fundus- contains gas and produces contractions to move stomach contents
- Body-reservoir for ingested food and fluids
- Antrum-lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small intestine.
The Intestine
Mouth to Anus transit time = 24-32 hours.
Small Intestinal Transit Time = 3 hours.
Most absorption occurs in the Small Intestine
Small Intestinal pH = 5.0 to 6.5
Colon drug absorption mainly occurs in the ascending region nearest to the SI
The Intestine: Characteristics
Characteristics:
- Most transporters are located in SI.
- Upper SI = mixing.
- Lower SI = electrolyte.
- Colon = fluid and electrolyte absorption.
Intestinal Absorbing Surface Area
Microvilli increases surface area in the small intestine by 600x
Relative Size of Micro vs. Nano Particles
See figure.
Columnar Epithelium
Columnar eptihelial cells form a single continuous layer of absorptive cells ( 25µm high and 8µm wide) covering each villus.
Separated from lamina propria (blood vessels and lymph) by basal lamina-300Å thick-comprised of glycoproteins and penetrable by lymphocytes (8-12µm).
Columnar Epithelium: Crypt Region
-3x more crypt then villi, comprised of undifferentiated cells that prolierate
-Goblet cells-mucus secreting; Paneth cells-regulate microflora; and
Argentaffin cells that secrete mucus component.
Columnar Epithelium: Villus Region
-Absorptive enterocytes
-A few goblet cells do appear, as well as M-cells which overlay the Peyer’s
patch or lymphoidal tissue
-Cells from the crypt migrate to the villus tip and are extruded-sloughed off at the tip-enterocyte lifetime 2-3 days, entire lining of the GI tract turns over every 2-4 days.
Colon Characteristics
125 cm long from caecum to anus, with transport being much slower then in small intestine.
- Ascending colon 20 cm long
- Traverse colon 45 cm long
- Descending colon 30 cm long-rest is sigmoid
Varies in thickness from 2.5 cm in the sigmoid region to
8.5 cm in the caecum
Ileocaecal valve limits food flow from the ileum into the caecum and vice-versa.
Colon is responsible for water and electrolyte absorption (caecum, ascending colon)-prevents dehydration and leads to formation of solid fecal matter.
Colon Characteristics 2
Colon structure
- Serosa-squamous epithelium covered with adipose tissue
- Muscularis Externa-inner circular muscle layer and incomplete outer longitudinal layer
- Submucosa and mucosa
Colonic Mucosa-three layers
- Muscularis mucosae
- Lamina propria
- Epithelium
Proximal colon is usually where enteric coated formulations target by oral administration.
Distal colon-rectal administration, e.g. suppositories.
Rectum
Rectum has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near the anal sphincter) half. Highly folded
The stratified squamous, non-keratinized epithelium, in particular, allows high drug absorption.
There are a number of high potency drugs that
may be delivered rectally.
Many young and old patients have gag reflex problems with pills, extemporaneous compounding of the drug in suppositories is used.
Low residence time
Challenges to Assumptions Made with GI Physiology-Clinical Considerations
Transporters and enzymes vary along the GI tract.
Variability is enormous in GI fluid composition
Diet and chemical exposure varies
Pharmacogenetics and genomics are huge issues
Interindividual variation is also significant (intra?)
Drug-nutrient and drug-drug interactions are common.
So much more…Shout out to the gut microbiome
Bottomline: One Size formulations do not fit all.
Drug Solubility Changes Along the GI Tract
Factors influencing drug solubility: -Buffer capacity -Bile salts -Regional fluids -Other drugs -Potential issues from endogenous substrates
Critical Points of ADMET
Critical Points:
- Disposition is comprised of distribution and Elimination
- Elimination describes the removal of the drug from the body and includes both:
- **Metabolism
- **Excretion
- Toxicity is a result of exposure
- There can all be defined by the plasma vs. time curves, which is the focus of our lectures.
Nature of Pharmacokinetic Process
*Described by concentration time profiles
– shape of the profiles depends on point of observation
*Compartments represent kinetically similar tissues or spaces
*Processes can be reversible or irreversible
*Processes can be linear or nonlinear
*Fast and slow processes tend to “disappear”
Biopharmaceutics Terminology
- Bioavailability refers to the rate and extent of drug absorption
- Absolute bioavailability is the AUC of a given dosage form compared with the AUC of the same dose injected intravenously.
- Relative bioavailability refers to the AUC of a given dosage form compared to an arbitrary reference standard
- Bioequivalent does not mean that the therapeutic effect of two dosage forms are equivalent.
Dose covers two aspects
-Dose covers two aspects:
**The amount of chemical in which
the whole organism is treated.
**The local concentration of the chemical at the biological response site.
-The relationship between dose and receptor concentration is a function of the ADME.
Excipients - The key ingredient(s) for controlling drug delivery
- Coatings can be applied to control diffusion rates and modify the release properties of the drug from the interior.
- Disintegrants can be used to control regions of release based on physicochemical properties
- Lubricants can slow dissolution based on properties
- Internal excipients can be used to modify the release rates as well
- **Swellable matrices
- **Non-swelling matrices
- **inert plastics.
Coating
- Coatings are applied to the outside of solid dosage forms to accomplish the following:
- **protection of agent from air and/or humidity
- **mask taste
- **provide special drug release
- **aesthetics
- **prevent inadvertent contact with drug (i.e.: proscar and pregnant women)
- Aqueous film coatings generally contain
- **film-forming polymer
- **plasticizer to produce flexibility and elasticity of coating
- **colorant and opafier
- **vehicle
Coating: Non-aqueous film coating
- film-forming polymer-produce smooth films
- alloying substance to provide water solubility or permeability to the film
- plasticizer to produce flexibility and elasticity of coating
- surfactants enhance film coat spreading
- colorant and opafier improve appearance
- sweeteners, flavors, and/or aromas
- glossant providing luster
- volatile solvent allows spreading & evaporation
Enteric Coatings
Added to dosage forms to prevent the early release of an API in a region where it may undergo chemical or metabolic breakdown.
Primary reasons for enteric coating
- To prevent acid sensitive APIs from gastric fluids
- To prevent gastric distress from the API
- To target API delivery to a site in the intestine
- To provide a delayed/sustained release.
- To deliver the API in a higher local concentration in the intestines where it may be absorbed and have a higher bioavailability.
Sustained Release
describes a pharmaceutical dosage form formulated to slow the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged and its plasma profile is sustained in duration. In other words: the onset of pharmacologic action is delayed, but its therapeutic effect has a sustained duration.
Controlled Release
goes beyond sustained release and implies a reproducibility and predictability in the drug release kinetics. Therefore the kinetics from one dosage unit is reproducible and predictable from one unit to another. Allows us to maintain a narrow drug plasma concentration-Steady State
Examples of Traditional Controlled Release Formulations
-Coated Beads, Granules, or —Microspheres
***Coating on the beads controls release by programmed erosion
Example: Contact
- Multitablet system.
- **Small tablets placed in a gelatin capsule
- Microencapsulated
- **Solids, liquids, or gases are encapsulated into walled material, which allows spreading of microparticles across absorbing surface.
- Drug Embedding in a Slowly eroding or Hydrophilic matrix
- **Drug is homogeneously dispersed in the eroding matrix and its release is controlled by erosion rate.
Steady State
At steady state, the rate going into the body must equal the disposition (the rate distributing early and being metabolized, and/or being excreted from the body throughout).
Characteristics of Drugs Best Suited for Oral Controlled Release Formulation
- Exhibit neither slow or fast rates of absorption and excretion
- Uniformly absorbed from the gastrointestinal tract
- Administered in relatively small doses
- Have good safety/therapeutic window
- Chronic therapies better suited than acute
Processes Required for Oral Absorption of Monolithic Dosage Forms
- Drug molecules at the surface dissolve to form a saturated solution.
- Dissolved drug molecules pass throughout the dissolving fluid (diffuse) from the area of high concentration to low concentration
- Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed
- Replenishment of drug molecules in the diffusion layer is achieved by further dissolution
Effect of Particle Size
- Surface Area Increases when solids are broken up into smaller pieces
- Red Surfaces are new surfaces without effecting volume
- Effect continues as you move from tablet to granules to particles
- Increased surface area leads to increased dissolution rate
Factors limiting oral drug absorption
-3 factors can limit the ability of a drug to absorb after oral administration
*Solubility
+++Can’t Get Enough Drug Into Solution
*Dissolution
+++Can’t Get Drug Out Of Tablet
*Permeability
+++Can’t Get Drug Across GI cell membrane
Solubility Limited (KNOW THIS
- Drugs with very poor solubility are often limited as druggable candidates
- Represented as a small Cd value in previous equations
- Dosage form dissolves fast and drug permeates readily
- Increasing dose doesn’t increase blood levels as the GI fluids are already saturated
Dissolution Limited
- Drug is unable to dissolve into the solution from the dosage form in sub-saturated fluid
- Dissolution Time is greater than the time for absorption in the intestines
- Often due to poor formulation/manufacturing
- Need to have a tablet that can dissolve but also stand up to shipping and handling
Permeability Limited
- Characteristic of the API itself similar to Solubility Limited
- Dissolution is fast with sub-saturated fluids
- Increasing the amount of drug increases absorption
- See Notes up to now and previous slide with Permeability equation
- **Increasing Cd by increasing the amount of drug
- **Increases dM/dt which is absorption in this case
Permeability Rate-limited Absorption: Rate limiting factors
- physicochemical properties-drug
- physiological properties-membrane
Dissolution rate-limited absorption: Rate-limiting factors
- physicochemical properties-drug
- physicochemical properties-formulation
Definition of a generic drug
A drug product that is comparable to a brand/ reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.
Generic product: therapeutic equivalence
- Therapeutic Equivalence
- **Pharmaceutical Equivalence
- **Bioequivalence
-A generic product judged therapeutically equivalent to the reference listed drug will have the same identity, strength, quality, safety, and efficacy.
Pharmaceutical Equivalents
-Same active ingredient(s); same dosage form; same route of administration; identical in strength or concentration; and may differ in characteristics such as shape, excipients, color…
Bioequivalence
-Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at the same molar dose under similar experimental
conditions
- In vivo measurement of active moiety(ies) in biologic fluids, or
- **In vivo pharmacodynamic comparison
- **In vivo limited clinical comparison
- **In vitro comparison
Questionnaire-Based Study Assessing Switch to Generic Formulation of the Same Drug Product
-2885 patients receiving phenytoin, carbamazepine or valproic acid were queried.
- Patient Reporting Results:
- **70.5% no problems after switch
- **10.8% range of problems including reappearance of seizures
- **9.9% unspecified issues
- **8.8% other issues, but no follow-up included
-30% of respondents reported an issue with a switch to a generic drug product.
Processes Required for Oral Absorption of Monolithic Dosage Forms
- Drug molecules at the surface dissolve to form a saturated solution.
- Dissolved drug molecules pass throughout the dissolving fluid (diffuse) from the area of high concentration to low concentration
- Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed
- Replenishment of drug molecules in the diffusion layer is achieved by further dissolution
A Closer Look…
- A drug product is considered bioequivalent if the 90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80%-125%. [both Cmax (111% - 126%) and AUC (97% - 108%) from the Meyer study].
- Differences in Cmax and Tmax were due to faster dissolution of the generic products comparative to the RLD.
IVIVC
-Even though all four products demonstrate a linear relationship between the percent dissolved and the percent absorbed, no single correlation could be established to predict the bioavailability of all four products no correlation was possible between dissolution rate and AUC
***More Importantly, there is definitely an issue in the interchangeability of these products.
Mimicking Clinical Conditions
- Dosage form design requires consideration of patient related variables
- Patient related variables are not accurately assessed during development and scale up.
- “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 and scale-up.
Oral Delivery Summary
- Drug performance (PK/PD) is controlled by the interplay of excipients (formulation), the physicochemical properties of the drug, and the physiological barriers between the GI tract and the site of action.
- Oral formulations can control the absorption rate (Kabs), which then has to be optimized with respect to disposition to yield a safe and efficacious response.
- Dosage form design is dynamic and is unpredictable, so patient habits have to be considered for dosing regimens.
- Patients will vary in response, so this needs to be considered.
- Generic formulations are not the innovator, and thus can cause some problems with performance
Pharmacotherapy and pregnancy
~60 million women at reproductive age
~10% of these women become pregnant annually
***Many are on meds for treating pre-existing conditions (e.g., epilepsy, hypertension, depression, asthma, etc.)
~But…PK of drugs in pregnancy is complex
- **Physiological changes alter ADME of drugs
- **Toxicity is a significant concern
Fetal Imprinting
- The developing fetus undergoes rapid changes during the 9 month gestation period
- Genetics, diet, environment, etc. can all impact the fetus.
- Fetal imprinting has been linked to:
- **Cardiovascular disease-Barker Hypothesis
- **Neurological disorders
- **Obesity/diabetes, as well as others
- Very difficult to predict human effects based on:
- **Many factors involved aside from genetics, e.g., diet
- **Many exposure studies done in animals.
Pediatric Pharmacology Issues
- Historical cases with drugs like thalidomide in the 1950’s induced in utero malformations.
- Exposure to xenobiotics are poorly understood. For example, endocrine disrupting chemicals (EDC; e.g., diethylstilbesterol) led to in utero programing of cancer in adolescence.
- Animal models have differing sensitivity to xenobiotic exposure than humans
- Human data is sparse, but xenobiotic exposure can lead to changes in developmental PK/PD.
- The target moves even further due to the environment!
Pediatric Drug Development
- “The joint goal for industry, regulators, practitioners and patients is to encourage pediatric drug development in order to create a situation where substantially more children have access to safe and effective medication…”
- Early USA regulation- 1962 Kefauver-Harris Drug Amendments 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
Best Pharmaceuticals in Children Act
-Testing drugs in children presents considerable scientific, clinical, ethical, technical, and logistical challenges.
- 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.
- Is 6 months of exclusivity worth the risk?
- After 6 months, is it cost effective to drop pediatric programs?
Pediatric pharmacology - Approved Drugs
- Children are “therapeutic orphans”
- Only 20-30% of approved drugs have pediatric labeling
- FDA has encouraged pediatric studies
- **Financial incentive to conduct studies
- —–Orphan and off-patent drugs - no incentive to do studies
- **Increased studies resulted in new labeling for 40 drugs.
- **For approval of selective number of new drugs pediatric studies have been required.
- Resources
- **Center for Drug Evaluation and Research at FDA - www.fda.gov/cder/pediatric/
- **Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies.
Pediatric pharmacology - What’s unique?
- Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking
- **Children are not “miniature adults”
- —–Dosing based on scaling (by body weight or body surface area) not always predictable for a given drug.
- **Animal studies not always predictive.
- **Clinical studies in children fraught with ethical and financial hurdles.
- **Administration of drug can also be problematic.
OATP1B1 SNP and Methotrexate (MTX)
- 1883 Patients treated with high dose MTX in a Children’s Oncology Group (COG).
- GWAS with over 5 million SNPS and MTX clearance was performed.
- Multiple dosing was performed.
- MTX clearance differences were associated with SLCO1B1 SNPs, which are the most important genetic variations out of 1279 of the patients
***Low clearance rates are associated with higher toxicity. Dose lowering adjustments and higher hydration rates should be required in children carrying these phenotypes.
Extrapolation Between Between Species
- The relevance of animal models (differences in the developmental timing of anatomical, physiological, biochemical and physicochemical events) can limit extrapolation to humans
- **Length of gestation and timing of events
- **Relative organ function maturity at birth
-Significant species differences exist in some transport proteins and regulatory machinery
Challenges with Pediatrics
- Biological Challenges
- **Ontogenic Changes
- **Compositional Changes
- Clinical Challenges
- **Clinical Trials
- **Caregiver Requirements
- Formulation Challenges
- **Dosage Form Selection
- **Flexibility in Dosing
- **Excipient Selection
- **Taste Masking
Pediatric Drug Development Initiatives (TEST QUESTION?)
-Paradigm shift for industry (know this):
**Traditional views over the last couple of decades have been to protect children from clinical research.
**(However, the current regulatory paradigm shift is to now
protect children through clinical research.
- New chalenges based on the Paradigm shift
- **Children are not minature adults
- **Pediatric patients need to be age classified
- **Pediatric patients require age appropriate formulations that used to be primarily made through compounding
- **First in child safety and efficacy preclinical models are lacking
Pediatric Formulations
- 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
Mini-Tablet Platform Formulation
- Ability to incorporate BCS Class I and III
- **Less effect of formulation
- **Likely more beneficial for testing of medications already on the 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
- Same or similar manufacturing conditions
- **Size is constant, number can fluctuate
- Fractional factorial DOE approach
- **Many process and formulation variables
Pharmaceutical Film Considerations
Advantages
- Acceptable for patients with dysphagia
- Ease and accuracy of dosing
- Increased stability compared to solutions/suspensions
- Faster onset of action
- Life cycle management
Disadvantages
- Difficult to manufacture
- Moisture sensitive
- Limited dosing capacity
- Increased packaging costs
Pediatric Pharmacology - Challenges Remain
-Age based dosage form selection
- Need for descriptive pharmacology (especially for new drugs) in pediatric patients
- **Children are not “miniature adults”
- —–Dosing based on scaling needs to better incorporate age based ontogenic changes.
- **Animal models need to be refined for prediction.
- **Enable clinical studies in children by tackling some of the ethical and financial hurdles.
- **Better means of drug administration are needed.
