Daunomycin Pharmacokinetics in Children

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Daunomycin Pharmacokinetics in Children

• Stacey Berg, MD

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Background

• Anthracyclines widely used in pediatric cancer
• Doxorubicin mostly in solid tumors
• Daunomycin mostly in leukemias

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Background

• Anticancer drug dosing in children based on body
  size
• Concern when patient deviates from ideal body
  weight
• Adult data decreased doxorubicin clearance,
  increased half-life with increased IBW
• Scanty data for children

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Doxorubicin PK in children

• 3 studies, all single samples
• Clearance 400 ml/min/m2
• 15-fold variability
• No clear correlation with age, BMI, weight
• Difference in Cmax between WBC gt50,000, WBC
  lt10,000

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• Glaser Pediatric Research Foundation study of
  doxorubicin and body composition in children
• COG study of daunomycin

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GPRN study objectives

• Evaluate relationship between obesity and
  doxorubicin PK in children
• Correlate PK parameters and body mass index, body
  composition
• Explore PK parameters and patient characteristics
  (age, gender, ethnicity), labs

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Eligibility

• 1 - 21 years old
• Informed consent
• Doxorubicin over 1 or 2 days, not continuous
  infusion
• Bilirubin ULN
• ALT/AST 3x ULN
• Weight 12 kg
• Doxorubicin dose based on true body weight

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Data Collection

• Height, weight, BSA
• AST/ALT/bilirubin/TP/alb/Cr/CBC
• Concomitant medications
• DEXA scan for body composition
• PK samples (0 - 48 hr adjusted for 1 or 2 day
  schedule)

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Patient characteristics
22 completed subjects

• 16 male, 6 female
• 10 Hispanic, 10 Caucasian, 2 Asian
• Median age 15 yr (range 3-21)
• Median body fat 25 (range 15-36)
• Median BMI 20 kg/m2 (range 13-30)

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HPLC Assay Development

• Solid phase extraction
• Reverse-phase HPLC with fluorescence detection
• Inter-, intra-day CV in plasma lt 7
• LLQ 2 ng/ml (4 nM)

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Sample chromatogram in plasma
Dauno (IS)
Dox
Doxol
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5 compartment model
doxorubicin
doxorubicinol
3
5
infusion
k31
k13
k54
k45
k12
k14
V1
V4
2
k21
k40
k10
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Modeled PK 1 infusions
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Modeled PK 2 infusions
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PK Parameters
From ADAPT model

• Dox median clearance 390 ml/m2/min (range
  35-1280)
• Dox terminal t1/2 28 hr (11-70 )
• Doxol terminal t1/2 39 hr (2-91 )
• Doxol clearance 37 ml/min/m2 ( 0-284)
• Similar to published adult data

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Dox clearance v. BMI
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Dox clearance v. body fat
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BMI is related to body fat
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Dox half-life v. body fat
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Dox clearance v. age
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Non-significant correlations
BMI, zBMI, or body fat with

• Dox volume of distribution
• Doxol clearance
• Doxol volume of distribution
• Doxol half-life

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Where we are

• Doxorubicin clearance decreases with increasing
  BMI
• Doxorubicin clearance tends to decrease with
  increasing body fat
• Most analysis still ongoing
• Correlations with labs
• Multivariate analysis
• Population model

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COG daunomycin study
Similar and expanded

• Describe dauno PK in children
• Explore BMI/body composition effects on PK
• Explore correlations with age, gender,
  race/ethnicity
• Explore relationship between PK and AEs
• Explore relationship between PK and organ
  function labs

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COG daunomycin study

• Groupwide
• Two year accrual
• Built-in reminder of study in registration system

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COG Study

• Age 21 yr
• Any diagnosis
• No specific organ function
• Any 1 or 2 day dauno infusion lt 24 hrs
• Coordinate with leukemia study

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ALL study

• Impact of obesity on PK in HR-ALL
• Explore PK vs. SER/RER, EFS, OS
• Prednisone, vincristine, daunomycin, asparaginase
  in induction
• Narrower eligibility (age 10 yr, registration
  on AALLL0232)
• Shared daunomycin PK

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Study plan

• Height, weight
• CBC, LFTs, Cr
• DXA for body composition at participating
  institutions
• Intensive PK sampling
• Collect concomitant meds
• Collect AEs for cycle with PK

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Sample size 100 subjects

• Detects minimum correlation of 0.32 with a 0.05
  and 90 power
• High probablility of detecting small increment in
  R2 associated With addition of new variable to
  regression model in mutlivariate analysis
• Track age- make sure accrue enough younger
  children

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Challenges

• Accrual
• Younger children
• Technical
• Drawing through central line
• Getting daunomycinol

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Future directions

• Population modeling
• Limited sampling for future studies
• Prospective studies of dose adjustments
• - Effect of dosing based on IBW
• - Effect of capping doses for BSA