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Daunomycin Pharmacokinetics in Children

Daunomycin Pharmacokinetics in Children. Stacey Berg, MD. Anthracyclines widely used in pediatric cancer Doxorubicin mostly in solid tumors Daunomycin mostly in leukemias. Background. Anticancer drug dosing in children based on body size Concern when patient deviates from ideal body weight

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Daunomycin Pharmacokinetics in Children

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  1. Daunomycin Pharmacokinetics in Children Stacey Berg, MD

  2. Anthracyclines widely used in pediatric cancer Doxorubicin mostly in solid tumors Daunomycin mostly in leukemias Background

  3. 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 Background

  4. 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 >50,000, WBC <10,000 Doxorubicin PK in children

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

  6. 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 GPRN study objectives

  7. 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 Eligibility

  8. 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) Data Collection

  9. 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)

  10. HPLC Assay Development • Solid phase extraction • Reverse-phase HPLC with fluorescence detection • Inter-, intra-day CV in plasma < 7% • LLQ 2 ng/ml (~4 nM)

  11. Sample chromatogram in plasma Dauno (IS) Dox Doxol

  12. 5 compartment model doxorubicin doxorubicinol 3 5 infusion k31 k13 k54 k45 k12 k14 2 V1 V4 k21 k10 k40

  13. doxorubicin doxorubicinol Modeled PK: 1 infusions

  14. doxorubicin doxorubicinol Modeled PK: 2 infusions

  15. 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

  16. Dox clearance v. BMI

  17. Dox clearance v. body fat

  18. BMI is related to body fat

  19. Dox half-life v. body fat

  20. Dox clearance v. age

  21. Non-significant correlations BMI, zBMI, or body fat with: • Dox volume of distribution • Doxol clearance • Doxol volume of distribution • Doxol half-life

  22. 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

  23. 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

  24. COG daunomycin study • Groupwide • Two year accrual • Built-in reminder of study in registration system

  25. COG Study • Age ≤ 21 yr • Any diagnosis • No specific organ function • Any 1 or 2 day dauno infusion < 24 hrs • Coordinate with leukemia study

  26. 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

  27. 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

  28. 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

  29. Challenges • Accrual • Younger children • Technical • Drawing through central line • Getting daunomycinol

  30. 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

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