# Presentation: 602013

## Daunomycin Pharmacokinetics in Children

**Stacey Berg, MD**

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

**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
Adult data     decreased doxorubicin clearance, increased half-life with increased % IBW
Scanty data for children 

**Concern when patient deviates from ideal body weight**
**Adult data     decreased doxorubicin clearance, increased half-life with increased % IBW**
**Scanty data for children**** **

**Background**

## 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

**Clearance ~ 400 ml/min/m****2**** **
**15-fold variability**
**No clear correlation with age, BMI, weight**
**Difference in Cmax between WBC >50,000, WBC <10,000**

**Doxorubicin PK in children**

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

**COG study of daunomycin**

## 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 **

## 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**

## 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)**

## Patient characteristics

**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/m****2**** (range 13-30)**

***22 completed subjects***

## 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)**

## Sample chromatogram in plasma

**Doxol**

**Dox**

**Dauno (IS)**

## 5 compartment model

- V1

- V4

- 2

- 3

- 5

- doxorubicin

- doxorubicinol

**infusion**

- k40

- k21

- k10

- k12

- k31

- k13

- k54

- k45

- k14

## Modeled PK: 1 infusions

## Modeled PK: 2 infusions

## PK Parameters

**Dox median clearance 390 ml/m****2****/min (range 35-1280)**
**Dox terminal t****1/2**** 28 hr (11-70 )**
**Doxol terminal t****1/2 ****39 hr (2-91 )**
**Doxol clearance 37 ml/min/m****2**** ( 0-284)**
**Similar to published adult data**

***From ADAPT model***

## Dox clearance v. BMI

## Dox clearance v. body fat

## BMI is related to body fat

## Dox half-life v. body fat

## Dox clearance v. age

## Non-significant correlations

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

**BMI, zBMI, or body fat with****:**

## 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

## COG daunomycin study

**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**

**Similar and expanded**

## COG daunomycin study 

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

## COG Study

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

## 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**

## 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**

## Sample size 100 subjects

**Detects minimum correlation of 0.32 with  a 0.05 and 90% power**
**High probablility of detecting small increment in R****2**** associated With addition of ‘new’ variable’ to regression model in mutlivariate analysis**
**Track age- make sure accrue enough younger children**

## Challenges

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

## 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**