Lecture 18 - Paeds Flashcards
what are the different childhood age classifications ?
neonate is 0-28 days
infant is >28 days - 12 months
toddler >12 - 23 months
preschool child 2-5 years
school age child 6-11 years
adolescent 12-18 years
summarise the concept of heterogeneity in the pediatric population with regard to pharmacokinetics and pharmacodynamics
Ontogeny can play a role
Younger age = Greater Risk
Understand the ADME characteristics of your drug
Leverage Adult Data
Assess Risk
Likelihood and Consequence
Many gaps still exist
Mitigate the risk through
Modeling Scenarios
Product and Dosing Designs
outline the ADME differences in premature babies
absorption : increased gastric pH and reduced GI entering time, higher density f skeletal muscle capillaries, thinner status corner and higher hydration of epidermis
distribution: increased lean mass verses fat mass per kg bw, lower concentrationm of drug-binding proteins (a1-acid glycoproteins and albumin), higher plasma concentrations of bilirubin, altered blood flow, tissue perfusion, membrane permeability and cardiac output
metabolism: reduced hepatic drug emtbaolsign enzyme activity, immaturity of intestinal drug metabolising enzymes and efflux transporters, reduced hepatic blood flow
excretion: reduced glomerular filtration rate, reduced tubular secretion and reduced tubular reabsorption
The effect of paediatric physiology on pharmacokinetics of common drugs?
Gentamicin: In children, the volume of distribution decreases as body water percentage decreases. As a result, higher doses per kilogram of body weight are needed to reach therapeutic levels.
Codeine: Its conversion to morphine is unpredictable in children, and they also have reduced clearance. Codeine is not recommended for children due to these factors and safety concerns.
Theophylline: Children have increased clearance of theophylline, necessitating higher doses per kilogram of body weight in infants and children.
Phenytoin: This drug has decreased oral absorption in infants due to higher stomach pH and decreased protein binding, leading to decreased bioavailability. Despite this, lower serum concentrations are required because of the lower protein binding in infants.
Benzyl alcohol: This common excipient has decreased clearance in infants, which can lead to accumulation and potentially fatal ‘gasping syndrome’.
Levetiracetam: Children have increased clearance of this drug, meaning a higher dose per kilogram is required in patients up to 12 years of age.
Methylphenidate: This drug has decreased clearance in children aged 6–12 years compared to adolescents, which means a lower dose is required
what is alkindi ?
Paediatric exampleAlkindi is an immediate-release hydrocortisone preparation that has been specifically designed to meet the dosing needs with adrenal insufficiency for whom no licensed, child-friendly products exist in Europe or in the US.
what is diurnal?
Diurnal is a UK-based specialty pharmaceutical company dedicated to developing hormone therapeutics to aid lifelong treatment for rare and chronic endocrine conditions.
what is the dose for hydrocortisone for adrenal insufficiency ?
By mouth using immediate-release medicines
ForNeonate8–10 mg/m2daily in 3 divided doses, the larger dose to be given in the morning and the smaller in the evening, higher doses may be needed.
ForChild8–10 mg/m2daily in 3 divided doses, the larger dose to be given in the morning and the smaller in the evening, higher doses may be needed.
what are multiparticulate granules?
granule allows for swallowing of granules even by neonates.
The granules are presented within a transparent capsule that is opened for dosing, this allows for accurate paediatric dosing with dose strengths of 0.5, 1.0, 2.0, and 5.0 mg
The granules are so small that even the 0.5 mg capsule contains ~900 granules.
describe the formulation of the granules
Each granule has an inert cellulose core, a spray coat of hydrocortisone and a taste masking layer to prevent the bitter taste of hydrocortisone being experienced by the patient.
what are key considerations for designing an effective pediatric clinical trial.
Regulatory Oversight: Ensuring compliance with additional regulations, consent/assent procedures, and ethical requirements specific to pediatric populations.
Specialized Equipment and Staff: Utilizing suitable medical equipment and techniques, and having staff trained to manage pediatric patients.
Growth and Development Considerations: Acknowledging various stages of growth such as puberty, dental development, and metabolic differences when designing the trial.
Family-Centered Techniques: Implementing strategies for the recruitment, retention, and communication that are family-friendly and enhance the comfort of participants.
Dosing Methods: Creating dosing methods that are safe, palatable, and easy for children to take.
Quality of Life Considerations: Considering the impact on the child’s quality of life, schedule, and the number of interventions required.
Age Groups: Addressing the needs of multiple age groups, including preterm infants, neonates, infants and toddlers, children, and adolescents.
How are special populations considered in regulatory guidance?
Typical drug development requires clinical testing of medicines in a general population and can exclude special populations.
For example typical exclusion criteria in phase I and II trials include: adults aged 18-65; a BMI of less than 30 kg/m2; pregnancy; hepatic dysfunction.
Phase 3 trials can have broader recruitment with increased age; increased divergence in ethnicity and inclusion of patients with co-morbidities
what is connect for children?
c4c (conect4children) is a large collaborative European network that aims to facilitate the development of new drugs and other therapies for the entire paediatric population.
It is a pioneering opportunity to build capacity for the implementation of multinational paediatric clinical trials whilst ensuring the needs of babies, children, young people and their families are met.
what are ethics issues in paediatric studies ?
The paediatric population represents a vulnerable subgroup and it is necessary to protect the rights of the study participants.
The recruitment of study participants should occur in a manner free from inappropriate inducement either to the parent is or the study participant.
As a rule the paediatric subject is legally unable to provide informed consent.
So they are dependent on their parents to assume responsibility for their participation in the study, who will give their fully informed consent.
Participants of appropriate intellectual maturity should personally sign and date either a separately designed written assent form or the written informed consent.
It is important to minimize the distress and discomfort :
use of topical anesthesia to place IV catheters, which have to be indwelling catheters.
Personnel knowledgeable and skilled in dealing with the paediatric population.
A physical setting with furniture, play equipment, activity, and food appropriate to the age of population.
A familiar environment such as the hospital or clinic where participants is normally receive their care.
what are sampling protocol issues?
The volume of blood withdrawn should be minimized in paediatric studies.
Use of sensitive assays.
Use of laboratories experienced in handling small volume of blood.
Use of indwelling catheters to minimize distress.
Use of population pharmacokinetics and sparse sampling based on optimal sampling theory to minimize the number of samples obtained from each patient.
