Paediatric Biopharmaceuticals Flashcards
Name some challenges when designing paediatric products and predicting their performance
Gaps in knowledge
Formulation issues - ease of administration
Formulation types
Immediate or controlled release Multiparticulate formulations Suspensions Tablets Capsules Minitablets Solution Orally-disintegrating tablets Dispersible/effervescent tablets
What factors go in to formulation type used for a drug given to children?
- desired pharmacokinetic profile (Rate and extent of exposure)
- patient acceptability (swallowable? Taste, texture, ease of administration
- Pharmaceutical factors
- solubility, dissolution, permeability, 1st pass metabolism
Name some pharmaceutical factors to consider for paediatric biopharmaceuticals
Dose range (wide as huge range of age)
Suitability of excipients
API properties: physicochemical properties and material attributes
Define permeability
Rate of absorption
Neonate age range
0-27 days
Infant age range
1-23 months
Child age range
2-11 years
Adolescent age range
12-18 years
Adult age range
> 18 years
Differences between adults and children that can affect formulation performance
Physiological changes i.e. Changes in…
- saliva production
- gastric pH and emptying rate
- intestinal transit
- surface area
- motility
- drug metabolising enzymes, drug efflux transports
- influence on controlled release dosage forms (influence on pH-sensitive coatings
What are the consequences of a reduced gastric acid secretion?
Reduced gastric acid secretion in neonates may:
Increase bioavailability of acid labile drugs
Increased gastric solubility of acid drugs and decrease in gastric solubility of basic drugs
What is formulation bridging?
Assessing the rate and extent of absorption from one formulation to another
How do you compare rate and extent of absorption from different formulations?
Measure Cmax (max concentration) and AUC (area under curve) Compare between two products
-bioequivalence
What is bioequivalence?
Assessing the statistical equivalence of Cmax and AUC from 2 different products using confidence intervals and regulatory standards
Why is formulation bridging used?
For chronic illnesses, the patient may need treatment from a young age into adulthood
You need to know whether dose adjustment is needed when switching between two formulation types
Also, to select the appropriate formulation and reduce toxic side effects
Name some broad areas where adults and children differ physiologically, where it affects formulation design
Saliva flow rate Stomach capacity Metabolism (gut wall, hepatic) Permeability Intestinal motility
Describe how differences in permeability between adults and children affects formulation design. Describe challenges.
GIT increases in length and diameter from birth onwards
Sugar absorption tests give contradictory results
More high quality data needed - proceed with caution especially in the very young
Describe how differences in the gut wall between adults and children affects formulation design and the challenges it poses
- Conflicting evidence as to how CYP3A transporter changes with age. Expressed in all children >6 months and 50% younger than 6 months
- Urinogential tract - little known about paediatric expression
Describe how differences in hepatic metabolism between adults and children affects formulation design
- Overall, increased clearance, increase 1st pass metabolism and different metabolites
- Children have larger liver size and hepatic blood flow per body weight
- CYPs generally present from birth and reach adult levels at 2-5 years depending on isoform
Describe how differences in stomach capacity between adults and children affects formulation design
Stomach capacity=maximum volume stomach can spread to
-impact on volume of liquid patient is likely to drink when taking solid dosage forms, affects available dissolution volumes and gastric concentrations
Describe how differences in intestinal motility between adults and children affects formulation design
Irregular intestinal motility in paediatric patients leads to very variable transit times, which causes changes in product performance (especially controlled release formulations)
Name methods of formulation bridging
Relative bioavailability studies
In vitro testing
In silico PBPK (physiology-based pharmacokinetic) modelling
How are relative bioavailability studies used in formulation bridging?
Use of healthy adult volunteers (unethical to use kids for this) because large blood sample are need
Comparison between adult and paediatric formulations to support dosing selection in paediatric clinical trails
Compare final paediatric formulation to be used in pivotal studies to earlier formulations
How is in vitro testing used to help formulation bridging?
Compare dissolution studies - consider bio relevant media, volumes, agitation
What is IS PKPB?
In silco physiologically based pharmacokinetic models
How is in silico PBPK (physiology-based pharmacokinetic) modelling used in formulation bridging?
- Develop and validate model based on adult data, then alter the physiological parameters to predict for paediatric response
- can incorporate known differences
- mechanistically simulate processes in absorption and pharmacokinetic performance
- Can simulate virtual populations to look at potential variability
- can be augmented by sparse paediatric pharmacokinetics when clinical studies begin
- can use bio relevant in vitro dissolution as input for release rate
- can put all pieces together and work out overall impact
In silico physiologically-based pharmacokinetic (PBPK) modelling is limited by what?
Limited by gaps in measurable physiological parameters
Describe how paediatric drugs are tested and brought to market (main stages)
1) Preclinical:
- Formulation bridging
2) Exploratory dose finding (PK, PD, safety)
- adult market formulations used to form paediatric enabling formulations
3) Confirmatory and market stage
- Paediatric formulations
Impact of food on formulation bridging
- paediatric patients eat differently to adults
- take into consideration when extrapolating data from/on effect of food in adults to the paediatric setting
- effects formulation and drug absorption
- parents may want to mix child’s medicine with food
Food effect studies conducted via…
Giving adults an FDA breakfast
Effect of food on formulation and drug absorption
- drug binding to food components
- altered blood flow
- different gastric emptying rates
- altered composition of GI fluid
Where can you find paediatric drugs to be given with food? How many drugs are to be given with food? (Paediatric)
BNF - 11 drugs
What does one have to consider when thinking of mixing food for administration of a medicine to a child? Give example
-Unintended consequences and impact/danger
Must consider:
-stability of the API
-dissolution/release rate
-pH dependent release mechanisms e.g. Enteric coats-this can change if stomach made more/less acidic
