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Pharmacy Year 2 Semester 2 > Paediatric Biopharmaceuticals > Flashcards

Paediatric Biopharmaceuticals Flashcards

1
Q

Name some challenges when designing paediatric products and predicting their performance

A

Gaps in knowledge

Formulation issues - ease of administration

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2
Q

Formulation types

A 
Immediate or controlled release 
Multiparticulate formulations 
Suspensions
Tablets
Capsules
Minitablets
Solution
Orally-disintegrating tablets 
Dispersible/effervescent tablets
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3
Q

What factors go in to formulation type used for a drug given to children?

A
  • desired pharmacokinetic profile (Rate and extent of exposure)
  • patient acceptability (swallowable? Taste, texture, ease of administration
  • Pharmaceutical factors
  • solubility, dissolution, permeability, 1st pass metabolism
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4
Q

Name some pharmaceutical factors to consider for paediatric biopharmaceuticals

A

Dose range (wide as huge range of age)
Suitability of excipients
API properties: physicochemical properties and material attributes

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5
Q

Define permeability

A

Rate of absorption

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6
Q

Neonate age range

A

0-27 days

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7
Q

Infant age range

A

1-23 months

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8
Q

Child age range

A

2-11 years

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9
Q

Adolescent age range

A

12-18 years

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10
Q

Adult age range

A

> 18 years

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11
Q

Differences between adults and children that can affect formulation performance

A

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
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12
Q

What are the consequences of a reduced gastric acid secretion?

A

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

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13
Q

What is formulation bridging?

A

Assessing the rate and extent of absorption from one formulation to another

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14
Q

How do you compare rate and extent of absorption from different formulations?

A 
Measure Cmax (max concentration) and AUC (area under curve) 
Compare between two products

-bioequivalence

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15
Q

What is bioequivalence?

A

Assessing the statistical equivalence of Cmax and AUC from 2 different products using confidence intervals and regulatory standards

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16
Q

Why is formulation bridging used?

A

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

17
Q

Name some broad areas where adults and children differ physiologically, where it affects formulation design

A 
Saliva flow rate 
Stomach capacity 
Metabolism (gut wall, hepatic)
Permeability 
Intestinal motility
18
Q

Describe how differences in permeability between adults and children affects formulation design. Describe challenges.

A

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

19
Q

Describe how differences in the gut wall between adults and children affects formulation design and the challenges it poses

A
  • 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
20
Q

Describe how differences in hepatic metabolism between adults and children affects formulation design

A
  • 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
21
Q

Describe how differences in stomach capacity between adults and children affects formulation design

A

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

22
Q

Describe how differences in intestinal motility between adults and children affects formulation design

A

Irregular intestinal motility in paediatric patients leads to very variable transit times, which causes changes in product performance (especially controlled release formulations)

23
Q

Name methods of formulation bridging

A

Relative bioavailability studies
In vitro testing
In silico PBPK (physiology-based pharmacokinetic) modelling

24
Q

How are relative bioavailability studies used in formulation bridging?

A

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

25
Q

How is in vitro testing used to help formulation bridging?

A

Compare dissolution studies - consider bio relevant media, volumes, agitation

26
Q

What is IS PKPB?

A

In silco physiologically based pharmacokinetic models

27
Q

How is in silico PBPK (physiology-based pharmacokinetic) modelling used in formulation bridging?

A
  • 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
28
Q

In silico physiologically-based pharmacokinetic (PBPK) modelling is limited by what?

A

Limited by gaps in measurable physiological parameters

29
Q

Describe how paediatric drugs are tested and brought to market (main stages)

A

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

30
Q

Impact of food on formulation bridging

A
  • 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
31
Q

Food effect studies conducted via…

A

Giving adults an FDA breakfast

32
Q

Effect of food on formulation and drug absorption

A
  • drug binding to food components
  • altered blood flow
  • different gastric emptying rates
  • altered composition of GI fluid
33
Q

Where can you find paediatric drugs to be given with food? How many drugs are to be given with food? (Paediatric)

A

BNF - 11 drugs

34
Q

What does one have to consider when thinking of mixing food for administration of a medicine to a child? Give example

A

-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

Pharmacy Year 2 Semester 2 (33 decks)

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