Why are we all here?
• You want to learn more about what a career in medical science
research looks like (you might have figured out already that it
varies a lot!)
• I am part way through my PhD in Medical Science
(cancer/pharmacology), which is something you may want to
consider eventually. I can tell you all about what is involved 
• I am also an associate lecturer in Human Physiology. This is taken
by almost every undergraduate student in CMPH. Happy to chat
about that too.
My pathway
‘98
Born
2025
Scheduled to
finish PhD
2016
Finished
School
2022
Became Assoc.
Lecturer
2017
Accounting
2022
Started PhD
2018
Started @ UoA
B.Hlth.Med.Sc
2021
Finished thesis
and graduated!
2018
Semester at
MU in Canada
2021
Started
Teaching
2020
Graduated
from U of A
2021
Honours @
Flinders
Evaluating the Pharmacology of
Medications Used to Treat Childhood
Leukaemias
Emma Thomas
Supervisors: Dr Madelé van Dyk and Dr Ganessan Kichenadasse
Childhood Acute Lymphoblastic Leukaemia
Epidemiology:
• Most common childhood cancer
• Highest in 0-4 years
• 5-yr survival:
• 90% (standard risk)
• 40% (high risk)
Clinical Characteristics:
• Uncontrolled proliferation of lymphoblast cells
within the bone marrow.
• >25% lymphoblasts in bone marrow
• Lymphoblasts invade peripheral blood
• Results in decreased RBCs, platelets and neutrophil
Induction Phase of
Treatment
As per ALL06 Protocol
* Severe and frequent grade 3-4 toxicities associated with this protocol
* This means hospitalisation for many young children
Pharmacokinetics (PK) of Cancer
Drugs
Dose
Elimination
ingestion
absorption
1st pass ± activation
Pharmacokinetics
Metabolism
Excretion
Exposure
(Concentration in blood)
Absorption
concentration at target
Metabolism
Patient
Outcome
Pharmacodynamics
molecular effect
Distribution
* PK drives variability in exposure
* In adults, such exposure has been shown to vary up to
>100%
* Explains the large variability in response in adults
affinity to target
Effects
physiological effect
So, what’s the actual problem??
• Some kids respond well to treatment and other kids don’t.
• Some children only visit hospital once per week for the first month
and others get so sick that they’re admitted for the whole month.
• Often, toxicities can be related back to the particular drug that
causes them (depending on how the drug works)
So, what is difference between kids that get a lot of toxic effects and
kids that do relatively well?
2021 Pilot Retrospective Chart Review – Preliminary
Results - Toxicity
• Infections & febrile
neutropenia most
common – in line with
literature
• Data was readily
available, collection was
simple and efficient.
• Time taken: between 13 hrs per patient
2021 Pilot Retrospective Chart Review – Preliminary
Results - Hospitalisations
Adverse Event
n
%
Grade
Hospitalisation (days*)
Renal failure
4
20
NR
1
Mucositis
1
5
NR
6
Diarrhoea
1
5
Grade 3
1
Pancreatitis
2
10
Grade 3 (1)
1
Febrile neutropenia
8
40
Grade 3 (2)
5
Thrombocytopenia
3
15
NR
9
Anemia
20
100
NR
7
Bleeding
2
10
NR
2
Unspecified type
5
25
Grade 3 (1)
13
Viral
2
10
Grade 3 (1)
4
Pain
2
10
NR
1
Fever
5
25
NR
6
Hyperglycemia
1
5
NR
18
Hyponatremia
1
5
NR
2
*Note: two children were hospitalised for the entire induction phase—their ‘hospitalisation days’ have been
omitted from this table.
NR: not recorded
76 additional (unscheduled) days
50% re-admission rate
Higher than in literature (35%)
Experimental protocol – uses DEX
not PRED
Research Questions
1. Should dose individualisation be investigated in children
with leukaemia?
Precision
Medicine
AIMS
Aim 1
Develop LC-MS assays to
measure drug exposure
Aim 2
Aim 3
Conduct 3-year
clinical PK study
Correlate PK with
outcomes?
Aim 1: LC-MS Assay Development - Methods
Step 1:
Separation
Step 2:
Detection
Step 3:
Quantification
HPLC
Mass Spectrometry
Analytical Software
Aim 1: LC-MS Assay Validation - Methods
To get approval:
• Variability <15%
• Recovery >85%
TGA Approval 
Accuracy
Linearity
Matrix Effect
Inter/intra-day Variability
Recovery
Carry-over
Aim 2: Clinical study methods
Systematic Review
Prospective PK Study
Recruitment: Screening
and consent
Inclusion Criteria:
- Newly diagnosed or
relapsed ALL
- Aged 0-18 Years
- Prescribed daily DEX or
PRED
Baseline
Exclusion Criteria:
- Aged >18 years
- No ALL diagnosis
- Unable to comply with
study protocol
- Critically ill
PK Sampling (Cmin)
Day 8
Day 15
Day 22
Day 29
Collect Clinical Outcome Data (toxicity, efficacy, survival)
Correlate PK with Clinical Data
Aim 2: clinical study – methods - patient
outcome data collection
Use Data
Collection Tool
Developed 2021
Extract data
from hard
copy & OACIS
Record outcomes:
Demographic
diagnosis
treatment response
Aim 2: Clinical study - methods
• For this study, adherence to study protocol is essential to obtain a strong dataset.
• Regular review will help to ensure successful clinical implementation.
Barriers identified in initial phase:
• Recruitment/ consenting
• Blood collection at specified
timepoints
• Clinical data collection
Pallman et al., 2018. BMC Medicine
Plasma vs Dried Blood Samples
• DEX and PRED were able to be detected from dried
blood, using the same assay conditions!
• Peak areas were highly consistent (ie. Low variation).
• Peak shape needs to be optimised (perhaps by adjusting
chromatography settings).
• This technique could increase capacity for PK sampling
and thus, greatly improve the amount of data collected.
PhD ‘To-Do’ List:
- Complete remainder of 3-year study, reviewing and optimising protocols
- Develop LC-MS assays for the other drugs used to treat ALL (may )
- Data extraction from medical records
- Establish PK variability in children with ALL
- Full analysis of PK with clinical data (toxicity, cytogenetics, efficacy)
- Micro sampling techniques to increase PK sampling (April )
- Amend the ethics and add a pharmacogenetics component
Aim 3c: Feasibility Evaluation of Clinical Study
– Mitra Microsampling Methods
Prick Finger
Supernatant into
LCMS vial
Absorb blood
and dry for 3hrs
10,000 RPM
10 mins
Drop tip into
MeOH
Shake 1hr
@ 40°C
Community Engagement
ACKNOWLEDGEMENTS
SA Precision Dosing Group
•
•
•
•
•
Dr Madele Van Dyk (Primary Supervisor)
Dr Ganessan Kichenadasse (co- Supervisor)
Dr Morton Burt (co-Supervisor)
Jason Van Leuven (PhD Student)
Milton Franco Ortiz (Honours Student)
The Basil Hetzel Institute
•
•
•
Professor Betty Sallustio
Shane Spencer
The wonderful team of technicians
Womens and Childrens Hospital
•
•
•
•
A/Prof Tamas Revesz
Dr Heather Tapp
Dr Matt O’Connor
Jimmy ……
Examiners
Dr Anya Hotinski
Dr Tanja Jankovic-Karasoulos
Moral Support Crew
•
•
•
•
•
•
•
•
Nadine Smith
Bridget Mooney
Chelsea Boylan
Reham Mounzer
Dr Voula Gaganis
Dr Helen Harrison
Dr Lara Escane
Dr Marie O’Shea
Systematic Review – Corticosteroids
• Only 3 observational PK studies
• 1 simulation
• High PK variability (CL and Vd)
Study
Details
Dose
DEX PK
Short
10mg/m2/d
x 14d
Age 1-19yr
N =1,084
• POP PK simulation study
reported decrease in variability
Age 2-15yr
N = 228
treatment, WBC at diagnosis
DEX PK
Age 1-19yr
accounted for in dosing.
Interpretation:
Limited corticosteroid PK data highlights a gap
in knowledge and high variability indicates
that TDM may be beneficial in children
PK
High IIV
60 mg/m2
per day
PK
High IIV
Petersen
2003
Yes
8 mg/m2/d
PK
High IIV
Yang
2008
Yes
PK and clinical
response
86.5%
prediction
accuracy
for PK and
response
Ouzounog
lou 2012
Yes
Jackson
2019
Yes
PRED PK
when covariates (age,
and serum albumin) were
Finding
Long: 6
mg/m2/d x
28d
Ref
TDM
Indicated?
Outcomes
N = 214
oncosimulator
n/a
to predict PK mathematic
and response
al
Age: children simulation
Notes: CL: clearance; Vd: volume of distribution. It should be noted that both
these PK parameters are ‘apparent’ CL and Vd since the drugs were taken
orally and refers to CL/F and Vd/F, where F refers to ‘bioavailability’.