Lec 13- Medicines for children

Question 1

Medicine development

Against the odds

Answer 1

• Odds are 13.8% (Phase I to approval)
• Cost is >$1,400,000,000 plus >$300,000,000 post-approval research
• Discovering and developing a new medicine is challenging, and developing paediatric medicines is very difficult indeed

Question 2

Timeline for pharmaceuticals

Answer 2

Question 3

The paediatric medicines market

Small humans, big needs

Answer 3

• Large market- 20% of the EU population, 100 million individuals, less than 18-year-old
• Poorly served market
  
  • Comparatively small market size
  • Logistical challenges and technical difficulties have been a disincentive for major pharmaceutical companies from addressing the needs of the paediatric market
  • Disease burden highest in adults
  • Between 50-90% of medicines have not been developed for children
  • As a result, most use involves off-label usage of products that are not in an age-appropriate formate i.e. specials, extemporaneous preparations, manipulated adult forms

Question 4

Coping mechanism

Answer 4

• Mix- hide in food
• Mask: Preceed or follow medicine with a flavour
• Physical force
• Bribery- money
• Improve palatability- flavour enhancement (flavour ex)

Question 5

Coping mechanisms

Answer 5

• 53% use coping mechanisms (170 children)
• Use of coping mechanisms significantly correlates (95%) with
  
  • How pleasant medicines is to take
  • Whether medicine makes a child feel unwell
• 71% of children who said their medicines did not taste ok, used coping mechanisms
• 76.9% of children who said their medicines tasted ok didn’t use coping mechanisms

Question 6

Perspective

Answer 6

• Identify and prioritise the needs
  
  • Industry, Academia, HCPs, Regulatory authorities, Patient advocacy groups
• Address the needs
  
  • Pharma scientists in industry and academia have a responsibility to design and develop age-appropriate formulations
  • Clinical development in industry and academia to deliver the clinical evidence
• Sustainability
  
  • Support in prescribing and dispensing practice from HCPs incentivises and sustains R&D and supply
  • Health technology assessment HTA authorities for pricing and reimbursement alignment with regulatory authorities
  • Influencers support of the value fo paediatric specific medicines

Question 7

Current paediatric regulation

Answer 7

• To promote the development of products and prescribing information to meet the specific needs of children
  
  • The intent is to do this without
    
    • Delaying approval of products in for adult population
    • Conducting unnecessary studies
• Incentives for industry (IP) balanced against requirements (for completion of paediatric studies)
• Scope
  
  • New products
  • Existing products with remaining IP
  • Off patent active ingredient PUMA (Paediatric Use Marketing Authorisation)

Question 8

Summary of Paediatric regulation

Answer 8

Question 9

Have the regulations made any impact

Answer 9

• 8 PUMAs made in 12 years- good but not a huge change
  *

Question 10

Special considerations in this special population

Question 11

Special considerations

Answer 11

• Cater for appropriate paediatric sub-population
  
  1. Pre-term newborn infants
  2. Term newborn infants (0-28 days)
  3. Infants & Toddlers (>28 days to 23 months)
  4. Children (2-11 years)
  5. Adolescents
• Physiological and ADME differences between children and adults
• Developmental variability through to adulthood
  
  • Careful when using age or weight criteria alone
• Development of specific formulations for paediatric dosing
  
  • Children’s medication adherence
  • Acceptibility of dose form and dose administration
  • Excipient toxicity

Question 12

Know your patient

physiology

Answer 12

• There are pH differences which influence ADME
• These factors need to be considered

Question 13

Summary of GI tract pH data

Answer 13

Question 14

At-risk groups

Potential oral sensory problems

Answer 14

• Pre-maturity- At risk due to having potentially aversive experiences, e.g. tube-feeding, sucking out, exhaustion (no suckling)
• Neurological disorders- Oromotor, dysphagia and sensory abnormalities, e.g. cerebral palsy or issues are seen with a syndrome where hypotonicity and hypersensitivity are a problem
• Developmental delay- Can result in delayed feeding development
• Pro-longed and complex medical intervention- Psychological impact of prolonged or invasive medical treatment e.g. NG tube, frequent N+V
• Metabolic, liver and kidney diseases- Growing evidence of disturbances of taste perception and appetite.Part of the larger group exposed to prolonged medical interventions and periods of feeling unwell
• ENT disorders and unusual structure and function- Physical difficulties with feeding and swallowing which can result in disturbances in feeding development

Question 15

Territory, location and timing

Answer 15

• Do the children in all intended territories have similar access to clean water? What impact does this have on products designed to require reconstitution before use
• What dosage forms are children in the intended territories more familiar with
• Are multi-use packs more convenient for the patient than single-use packs
• Is intended administration in a hospital, at home, at school, in public
• Frequency and timing of dosing e.g. emergency rescue treatment

Question 16

Preferences

Answer 16

• Patient-centered
  
  • Acceptable to achieve adherence
    
    • Willing participation in taking the medication
    • On a routine basis in chronic treatment
• Administration friendly
  
  • Convenient and easy to measure dose, and administer or take
  • Without modification or coping mechanisms
• Individual preferences
  
  • Many external factors which have shaped, and continue to shape preferences
  • One size (preference) doesn’t fit all
  • What children would prefer may clash with adult paradigm and regulation

Question 17

Which dose form do children prefer

Answer 17

• Liquid vs Solid Oral
  
  • Logical deduction= nice tasting liquid
  • However, 8yr old CF patient describes her repulsion to medicines which produce gag reflex
  • A 7yr old neurology patient describes her decision to take tablets and refusal to take liquids
  • ARV medication- tablets predominant
  • In contrast, a number would simply prefer a nicer tasting liquid
  • Raises value of choice and flexible-dose forms

Question 18

Dose form considerations

Answer 18

• Medication adherence considerations
  
  • Solutions/suspensions- palatability
  • Solid oral dosage forms- ability to swallow
  • Orodispersible films and tablets
  • Ear/Eye drops- discomfort
  • Intranasal- taste
  • Suppositories- cultural acceptance
  • IV- needle-phobia
  • Inhalation- training, drug deposition
• HCP preconceptions and familiarity with dose form
• Development of medicines that can facilitate adherence
  
  • Skin patches
  • MR dosage forms- reduced dose frequency
  • Device

Question 19

Commercial products- our goal

Evidence-based prescribing & dispensing

Answer 19

• Registered ‘paediatric optimized’ commercial products provide the optimum solution
  
  • Acceptability
  • Ease of administration
  • Evidence of key clinical parameters- safety, efficacy and dose
  • Minimise imprecision and medication errors
  • Control of quality up to and including the point of use
  • Post-marketing pharmacovigilance, med info

Question 20

Multifactorial approach

Developing a TPP

Answer 20

• Therapeutic product profile
• Assessing all parameters in the setting the product will be used to develop optimum product for children
• Risk and benefit analysis

Question 21

Taste masking oral products

Answer 21

• Bitter blockers and taste modifiers
• Sweeteners and flavouring systems
• Modification of API solubility
• Molecular barrier around the API
• Physical barrier around the API

Question 22

Toxicity of excipients

Answer 22

• GRAS (Generally Regarded As Safe) concept- Adult focus
• Sweeteners- sucrose commonly used in liquid formulations; long term use promotes dental caries
• Preservatives- some commonly used preservatives in injectables and oral liquids may be toxic in children due to immature metabolism
• Solvent
  
  • Ethanol is commonly used in liquid preparations; may cause acute intoxication or chronic toxicity
  • Propylene glycol accumulation may occur in young children due to limited metabolic pathway
• Colouring agents- may be associated with hyperactivity

Question 23

Step database

Safety and Toxicity of Excipients for Paediatrics

Answer 23

Question 24

Accelerating and de-risking the production of a paediatric oral formulation

Answer 24

Question 25

Taste testing in children

Answer 25

• Taste-testing with medicines (sensory analysis study) requires a clinical protocol
• Increasing demand from regulators
• No defined standards of acceptability
• eTounge techniques
• Adult taste panels
• Easier to do in adults than children- ethics, adherence, result interpretations
• However, Children are different: taste buds and olfactory receptors are well developed in infants and the number then decreases with age.
• Tendency to prefer sweeter tastes; less tolerance of bitter & salty tastes

Question 26

Drug delivery route inhaled

Answer 26

• Airway anatomy differs in adults and children
• Mostly fixed doses or combined doses
• Metered Dose Inhaler
  
  • Requires coordination during use which limits utility in young children. Spacers can be used, but they are bulky and inconvenient for mobile use, and different spacer models can lead to different exposures
• Dry powder Inhalers (DPI)
  
  • Can be efficient devices for some children but beware inspirational force differences in younger children. Also, children under six do not generally have enough inspirational force
• Nebulisers with air compressors
  
  • Provide an alternative relatively passive men of delivery inhaled drugs but can also be bulky, inconvenient and heavy
  • Can result in imprecise dosing although some flexibility possible
  • There may be constraints in terms of total dose possible

Question 27

Drug deposition of radiolabeled salbutamol in a young child

Answer 27

Question 28

Drug delivery route oral

Answer 28

• Liquid formulations such as solutions, syrups, suspensions often considered the most appropriate for younger children who are unable to swallow capsules or tablets
  
  • Taste can be an issue for liquid formulations
  • Dose-volume is important
  • The flexibility of dose e.g. using oral dosing syringe to accurately measure the prescribed dose
  • Stability can be a challenge e.g. preserved v unpreserved
• Oral powders, effervescent tablets, orodispersible, chewable tablets, mini-tablets and films may be suitable for young children

Question 29

Drug delivery route oral (2)

Answer 29

• Tablets and capsules offer advantages such as stability, accuracy, portability, a greater opportunity of MR but are typically not widely prescribed for younger children

Answer 30

• Tablets made for scoring (delivery half the dose)- breaking of tablets = inaccurate dose delivered into patients
• Orodispersible minitablets- 2mm in diameter, these can use an increasing number of tablets to give certain dose
  
  • Dissolve in mouth within minutes
• In paediatrics we often dissolve tablets in liquids (in a syringe) to deliver to patient this can have poor homogenity
  
  • With ODMT we get 100 dissolution

Question 31

Preparation in oral dosing syringe and enteral tube recovery

Answer 31

• This shows that ODMT can dissolve rapidly in many different types of liquid
• Offers a range of taste masking for children (in milk one day than juice in another)- individual preferencing

Question 32

Mixing with food

Answer 32

• Mixed powdered/granulated formulations into or sprinkling them onto food is a viable option for paediatric delivery of drugs but beware
• Food can change the bioavailability of a drug by
  
  • Causing instability of the drug e.g. acidic citrus foods causing degradation
  • Delaying gastric emptying
  • Changing GI pH
  • Stimulating bile flow
  • Increasing splanchnic blood flow
  • Physical or chemical interactions with dosage form or API
  • Different diets (e.g. cultural/elective) introduce another variable

Question 33

Paediatric oral formulations

Answer 33

Question 34

Emergency treatment

Prolonged, acute, convulsive seizures

Answer 34

• Condition
  
  • Status epilepticus is seizure activity that lasts too long
  • It happens when a seizure doesn’t stop in the usual time or when someone has seizures one after another without recovering in between
  • Status epilepticus can happen with any type of seizures
• Treatment
  
  • Rectal Diazepam licensed indication
  • Rescue administration any time, any place
  • Required more socially acceptable administration of BZs

Question 35

Buccolam

Answer 35

Question 36

Chronic pathological drooling

Answer 36

• Chronic pathological drooling is common in children with cerebral palsy (10-40%) of which 15% is severe
• Frequent in individuals who are also developmentally disabled
• Common in children with epilepsy and/or learning difficulties
• Other rarer and often more debilitating neurological disorders can be associated with sialorrhoea
• Reason for variability in drooling in children with neurological disorders is unclear
• Degree of drooling is not constant over time

Question 37

Uncontrolled sialorrhoea in children

Answer 37

• Negative consequences for health and QoL: its effects should not be underestimated
• Chronically irritated and macerated facial skin
• Dehydration is a consequence of chronic fluid and nutrient loss
• Persistent drooling into school-age leads to social isolation which can be both practically and socially devastating
• A constant source of frustration for parents/caregivers, negatively affecting the relationship with a child

Question 38

Sialanar

Glycopyrronium

Answer 38

• Symptomatic treatment of severe sialorrhoea in children aged 3 years and older, with chronic neurological disorders
• Sialanar first product, containing any active ingredient, to be authorised in Europe to treatment drooling in any patient population- PUMA
• Clinical evidence-based dosing, easily titrated for individual patient needs, to balance efficacy and tolerability
• Minimal excipients, all suitable for children
  
  • Sodium Benzoate
  • Raspberry flavouring
  • Sucralose
  • Citric acid
  • Purified water

Question 39

Breastmilk drug delivery technology

Answer 39

• Therapeutics are directly delivered into breast milk as it exits the mother’s breast and is consumed by the infant