Grade

Fludarabine

Some PK studies in children have been published, however, the number of infants was limited. No effect of age on the PK of fludarabine has been found.

Level 1

Population PK model including infants

Author	Method	Number of Patients/Infants(<1yrs)	Age(yr), Median(range)	Age related findings
Ivaturi (2017)	Two compartment popPK model. Allometric scaling for BW. eGFR was included as covariate on CL.	133 / NS	5 (0.2-17.9)	No effect of age on CL, normalized to BW.
Langenhorst (2019)	Three compartment popPK model. Allometric scaling for BW. eGFR was included as covariate on CL.	258 / NS	18 (0.3-74)	After accounting for covariates, no size-independent effect of age was identified.

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
Chung (2019)	Two compartment popPK model. Allometric scaling for BSA. eGFR was included as covariate on CL.	43 / 0	11.8 (1.3-18.5)	No effect of age on CL, normalized to BSA.

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.