Grade

Cisplatin

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
Crom (1981)	Two compartment PK model (total platinum) and non-compartmental pharmacokinetics (free platinum)	28 / 0	11.4 (1.7-20.5)	The elimination rate constant of total platinum was larger in older children (more rapid elimination).
Dominici (1989)	Non-compartmental pharmacokinetics (total and free platinum)	14 / NS	NS (0.8-13)	Effect of age was not studied.
Murakami (1990)	One compartment PK model (free platinum)	6 / 0	9.4 (1.7-15.7)	Younger patients showed a lower CL and a higher V.
Peng (1997)	Non-compartmental pharmacokinetics and one compartment PK model (free platinum)	21 / 1	9.1 (0.5-19.3)	Effect of age was not studied.

Level 4

Case-series/report

Author	Method	Number of Patients/Infants(<1yrs)	Age(yr), Median(range)	Age related findings
Thomas (2018)	Case report, non-compartmental pharmacokinetics	1 / 1	2 weeks (gest. age 37 weeks)	CL was correlated to age and BW. CL (mL/min/kg) increased with increasing age.

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.