Lecture 19 - Pediatric oncology and pharmacology Flashcards
Describe leukemias in children
leukaemia begins in the Childs bone marrow and the growth of leukemias cells cam cause a child to not have enough normal red blood cells, white blood cells and blood platelets.
For many children we do not know why
Leukaemia occurs
The majority of childhood leukaemia’s areacquired
genetic diseases. This means that gene
mutations and chromosome abnormalities in
cells occur sporadically (by chance)
There are some known risk factors however
what is the molecular pathology of leukemias?
changes in the number of chromes.
About 20% to 25% of children with ALL have more than 50 copies of chromosomes per cell. A cell that has too many copies of chromosomes is called hyperdiploid. Children with hyperdiploid cancer
cells generally have a good prognosis, as they respond very well to chemotherapy.
Too few chromosomes
In approximately 5% of cases, leukemic cells have too few chromosomes. A cell that has less than 44 copies
is called hypodiploid cell. The prognosis is not as optimistic as in hyperdiploid.
describe chromosomal translocations as molecular pathology of leukemia.
chromosomal translocations is when a chromosome separates and attaches itself to an unrelated chromosome and so produces new chromosomes that express genes in different ways.
Problems arise when the translocation produces a new gene that instructs the cell to do things it normally would not —for instance, tell the cell to divide uncontrollably. For ALL, many translocations are more commonly found in different age groups.
The most frequent translocation that occurs inside leukemic cells in children 2–9 years of age is when parts of chromosome 12 and 21 fuse together. This translocation represents about 25% of all childhood ALL cases there are too many B-cell lymphoblasts (immature white blood cells) in the blood and bone marrow.
It is also possible to find leukemic cells with chromosome 9 and 22 translocated. This is also called a Philadelphia (Ph)-chromosome-positive. It is more common in children older than 10 years
what are the advances in the diagnosis and treatment of paediatric acute lymphoblastic leukemia?
improvement were made by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents and the provision of better supportive care.
ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. – personalised paediatric cancer medicine.
Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy
what are targeted therpesies that have been developed for ALL?
rituximab, ofatumumab,
Car T cell
epratozomab
tyrosine kianse inhibitors
agame secretase inhbitors
daratumumab
What is blinatumomab?
blinatumomab is a bispecific anti-T cell receptor and anti-CD19 antibody that engages T cells to activate a B cell specific inflammatory and cytotoxic resposne.
For paediatric patients aged 1 year or older, blinatumomab is approved for patients with Philadelphia chromosome-negative and CD19 positive acute lymphoblastic leukaemia that is refractory or in relapse after at least two previous therapies, or in relapse after having an allogeneic haemopoietic cell transplantation.
Blinatumomab has an acceptable toxicity profile compared with other treatments for B-cell acute lymphoblastic leukaemia, with fever, chills, neutropenia, anaemia, and hypo-γ-globulinemia being the most frequent side-effects
Nevertheless, cytokine release syndrome and neurological toxicity are severe events that have also been seen with blinatumomab.
what are the basic of pharmacokinetics in children?
most drugs for children are administered orally - easier to allow and cheaper to manufacture. also less painful than injection. more convenient to administer and less traumatic for the carer
the degree f adsorption through the gut wall depends on factors which differ between adults and children:
Ph of environment in the stomach or gut
volume fo acidic gastric fluids
rate of stomach emptying and rate go gut motility
what are other pssoibel routes of drug adminsiatrtion to children?
mucosal - bypasses first pass meytabosim eg mizadola. or lolly ie fentanyl. but expensive
rectal; rich blood supply near arteries- however absorption by this route in children is variable
Long lag time to adsorption ( around 40 mins vs 10 mins oral). but uncomfortable for child and care
Skin patch- i.e. fentanyl- care in children as skin thickness and blood flow highly variable i.e. a
fever increases blood flow- skin acts as reservoir-
BUT: drug leaks long time after patch removed- how can we therefore control or predict duration
Intramuscular- causes pain- loose trust of child, distressing- very good bioavailability but
BUT: avoided due to pain and trauma- especially if repeat administrations required
describe how absorption of pahramcokientics is affected in children.
Gastric PH higher ( less acidic)
by 3 years. Acid per kg of body weight similar to adults
Gastric emptying affects adsorption- slowed in under 1 year olds
Gasric volume is smaller
Biliary function- reduced bile acids and bile flow
Pancreatic enzymes lower i.e. lipase and trypsin
Intestinal villous morphology and surface area differ and Intestinal permeability differ: i.e. impaired
intestinal adsorption of lipid soluble drugs- decreases oral bio-availabilty- need more drug for desired dose
describe how drug distribution differs in children.
Premature and neonates have higher proportion of body weight as water compared to older children
Thus water soluble drugs will have > volume of distribution in neonates- more dilute- sub clinical doses
So have to have higher doses.
Other factors- physiological i.e.
neuromuscular junction less developed in neonates so needs less dose
muscle and fat content different neonates to older children to adults and between children
example anaesthetic drugs that redistribute to muscle and fat would have prolonged effects
Different proteins and thus protein binding i.e. lower concentration albumin in neonates so
concentration and binding affinity different
describe how metabolism differs in infants..
Hepatic blood flow reduced in neonates and less in infants Vs teens Vs adults
Enzyme systems involved in metabolism of drugs such as the CYPs- alters half life of drugs and very different in different ages
The renal efficiency in neonates is < compared to adults
- drugs reliant on glomerular filtration or tubular function are particularly affected by differences-
- results in prolonged half life of drug- more potent- may be toxic to children- overdose
How does pharmacodynamics differ in infants?
i.e. for many intravenous anaesthetics the dose for maintenance is higher for children than adults- due to rapid redistribution and rapid metabolic clearance
i.e. reduced fat and muscle content, more water, in neonates may prolong expected duration of action
i.e. neuromuscular blockers- tend to have a higher volume of distribution in young children- need more to achieve the clinically required concentration
Childhood obesity- increasing year on year- affects protein binding, blood flow rate, increased tissue volume and perfusion, obesity related changes in drug elimination organs traditionally use just weight-based dosing- often don’t choose correct body size metric
PK and PD also are very much altered in critically ill children
what are physiologic differences between children and adult that affect pharmacokinetics?
immature blood brain barrier
higher metabolic area
rapidly growing tissues
difference sin protein binding
immature cardiovascular system
delayed gastric empting
immature renal function
large body surface area
what are issues in accessing drug therapy for management of childhood diseases?
Real lack of Child appropriate formulations
Excipients (other stuff) often not child friendly- i.e. alcohol based, poisonous to small bodies
Medicines are trailed mostly on adults- marketed for adults- lack paediatric formulations
Clinical trial access- why not?- Previously many medicines were not studied in children so children are deprived
of the evidence base to use medicines rationally and safely
what are the new initiative to improves the issues associated with paediatric medicines?
BNFc
European Legislation Encouraging clinical trials of medicines for children- 2007- legislation for the need to study all new medicines where appropriate in children
Medicines for Children research Network
Paediatric Research Equity Act (PREA) in 2003.
The Best Pharmaceuticals for Children Act 2012 under the FDA Safety and Innovation Act.
