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Grade

Carboplatin

Carboplatin represents the "gold standard" of TDM in paediatric oncology (Figure 1). There is a clear understanding of the relationship between free drug exposure and toxicity/response in adult and paediatric patients. For the youngest of patients (<10kg), a mg/kg based dosing approach alongside TDM is advised (Figure 2). For cases where TDM is not feasible, starting at a lower dose of 4.4mg/kg on the first cycle and increasing to 6.6mg/kg on subsequent cycles if the dose is well tolerated is advised (Figure 2).

Level 1

Population PK model including infants

Author Method Number of Patients/Infants(<1yrs) Age(yr), Median(range) Age related findings
Chatelut (1996) Two compartment popPK model (free platinum). CL corrected for BW, creatinine and nephrectomy 57 / NS 5 (0.17-18) No additional effect of age on PK parameters that was not explained by BW or BSA.
Tonda (1996) One compartment popPK model (free platinum) 21 / 4 1.7 (0.2-4.2) Median CL (mL/min/m2) in infants lower than median for older patients.
Thomas (2000) Two compartment popPK model (free platinum) 38 / NS 3.5 (0.4-16.3) No effect of age on dosing method (renal function vs BSA dosing).
Patoux (2001) Two compartment popPK model (free platinum). Serum creatinine was identified as the most significant covariate on CL. 117 / NS 6 (0.1-18.4) No effect of age on CL relative to other covariates tested.
Veal (2010) Two compartment popPK model (free platinum). BW was included as covariate on PK parameters. 19 / 16 0.8 (0.2-1.2) CL (mL/min/kg) higher in infants <12kg compared to children >12kg.
Veal (2015) Therapeutic drug monitoring in preterm and full-term neonates. CL and AUC were calculated using the PK model of Veal (2007) and Peng (1995). 9 / 11 3 weeks (0.4-24 weeks) (gest. age 40 weeks (35-52 weeks)) CL (mL/min and mL/min/kg) increased with increasing age (normalized to full-term gestation).

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
Madden (1992) Two compartment popPK model (total and free platinum) 18 / 0 7.7 (2.9-23) No effect of age on CL after normalization to BW
Peng (1995) Two compartment popPK model (total and free platinum) 23 / 3 3.7 (0.08-18.4) Effect of age was not studied.
Doz (1998) Two compartment popPK model (free platinum) 15 / 1 16 / 1 5.0 (0.9-10.7) 4.6 (0.75-17.5) Effect of age was not studied.
Rubie (2003) Two compartment popPK model (free platinum) 12 / 0 3.4 (2.8-17.3) Effect of age was not studied.
Veal (2007) Two compartment popPK model (free platinum) 28 / 0 11.7 (1-21) Effect of age on PK was not studied. No age effect on platinum adduct formation.
Duong (2019) Two compartment popPK model (free platinum). Allometric scaling for BW. 46 / 0 3.5 (1.7-8.3) No effect of age on the PK parameters after including BW into the model.
Hong (2020) Non-compartmental pharmacokinetics and one compartment popPK model (total platinum). eGFR was included as covariate on CL. 25 / 0 6 (1-17) 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
Newell (1993) Two compartment PK model (total and free platinum) 22 / 4 3.8 (0.3-15.8) Effect of age was not studied only the impact of EDTA CL on dosing. Significant correlation between EDTA CL and carboplatin CL.
Riccardi (1994) Two compartment PK model (free platinum) 35 / NS 7 (0.8-17) Effect of age was not studied but PK parameters comparable to those reported in adults.
Kangarloo (2004) Non-compartmental pharmacokinetics and PK model (total and free platinum) 10 / 2 11 (0.25-16) Effect of age was not studied.
Levy (2009) Non-compartmental pharmacokinetics (free platinum) 28 / 0 8.5 (1-21) 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
Riccardi (1992) Case series, two compartment PK model (total and free platinum) 5 / 0 6 (1.5-7) Effect of age was not studied.
Picton (2009) Case series, two compartment PK model (free platinum) 1 / 1 Gest. age 32 weeks CL (mL/min) increased by 2-fold over 7 weeks.
Veal (2016) Case series, non-compartmental pharmacokinetics (free platinum) 1 / 1 8 weeks (gest. age 40 weeks) CL normalized for BW comparable with reported values.
Hawley (2019) Case series, non-compartmental pharmacokinetics (free platinum) 1 / 1 5 weeks (gest. age 40 weeks) Effect of age not discussed, but under standard dosing regimen patient would have been under-dosed

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