Grade

Ifosfamide

Some PK studies in children have been published, however, no infants were included and the effect of age on the PK parameters was only studied once. No effect on the PK of ifosfamide has been found.

Level 2

PK model including infants or PopPK model without infants

Author	Method	Number of Patients/Infants(<1yrs)	Age(yr), Median(range)	Age related findings
Kerbusch (2001)	One compartment popPK model	32 / 0	NS (1-18)	Effect of age was not studied.

Level 3

Non-compartmental PK study or PK model without infants

Author	Method	Number of Patients/Infants(<1yrs)	Age(yr), Median(range)	Age related findings
Boddy (1993)	Non-compartmental pharmacokinetics	16 / 0	4 (1-17)	No additional effect of age on PK parameters that was not explained by BW/BSA
Prasad (1994)	Non-compartmental pharmacokinetics	5 / 0	14 (3-15)	Effect of age was not studied.
Boddy (1996)	Non-compartmental pharmacokinetics	11 / 0	NS (1-16)	Positive correlation between patient age and exposure
Willits (2005)	Non-compartmental pharmacokinetics	19 / 0	10 (1-19)	Effect of age on PK parameters not studied. No correlation between age and DNA damage

Level 5

Mechanism-based reasoning or expert opinion

Author	Method	Number of Patients/Infants(<1yrs)	Age(yr), Median(range)	Age related findings
Balis (2017)	Mechanism-based development of dose bands based on BSA intervals

Table 1

Table 1 Model derived dosing nomogram for busulfan to achieve a target total AUCday0-4 of 90 mg/L*h (obtained from Bartelink et al. Clin Pharmacokinet; 2012:51: 331-345)

BW(kg)	Dose (mg/kg/day)
3	3.8
5	4.7
7	5.1
8-13	5.2
15-16	5.1

Figure 3

Figure 3 Vincristine exposure (AUC) values observed in neonate and infant patients following doses of >0.05mg/kg and doses of ≥0.05mg/kg, as compared to exposures observed in older children receiving a dose of 1.5mg/m2 (**** p <0.0001). Blue dashed lines indicate proposed therapeutic window.