A
Grade

Busulfan

Busulfan is a chemotherapy drug for which TDM in paediatrics is well established and encouraged. A wealth of paediatric data have been published for busulfan, leading to the development of a widely accepted dosing nomogram (Table 1). It is advised to start dosing as described in Table 1, with a view to obtaining a target exposure of 90mg/L*h over 4 days of treatment. Analysis of drug levels using in house monitoring services is recommended.

Level 1

Population PK model including infants

Author Method Number of Patients/Infants(<1yrs) Age(yr), Median(range) Age related findings
Nguyen (2004) One compartment popPK model 24 / 3 6.0 (0.45-16.7), mean (range) A log-linear relationship between BW and CL was demonstrated with no further age-dependency. A novel dosing regimen (mg/kg dose adjusted to discrete weight categories) for a better AUC targeting was developed.
Booth (2007) One compartment popPK model. Allometric scaling for BW. 24 / NS 6.3 (0.25-16.7), mean (range) No effect of age on CL after adjusting for BW.
Bartelink (2012) Two compartment popPK model. Allometric scaling for BW. 245 / NS 3.33 (0.1-26) Non-linear relationship between BW and CL (L/h): An increase in BW in neonates results in a larger increase in CL than an increase in BW in older children or adults.
Bartelink (2012) Two compartment popPK model. Allometric scaling for BW. 403 / NS 4.00 (0.1-35) Non-linear relationship between BW and CL (L/h): An increase in BW in neonates results in a larger increase in CL than an increase in BW in older children or adults.
Michel (2012) One compartment popPK model 67 / 9 4.0 resp. 7.5 (autoSCT resp. alloSCT) (0.3-17.2) Non-linear relationship between BW and clearance.
Paci (2012) One compartment popPK model. Allometric scaling for BW. 205 / NS 2.5 (0.03-15) The higher allometric exponent for CL accounted for a larger increase of CL in children <9 kg. For infants <9 kg, the model predicted a 2.4-fold increase in CL for a doubling in BW, whereas a 1.7-fold increase in CL was associated for the same BW growth in children ≥9 kg.
Savic (2013) One compartment popPK model. Allometric scaling for BW. CL corrected for maturation. 149 / NS (20 <0.5 yrs) 0.94 (0.08-3.3) CL increases by approximately 1.7-fold between 6 weeks and 2 years of life due to maturation.
McCune (2014) Two compartment popPK model. Allometric scaling for BW. CL corrected for maturation and sex. V1 and V2 corrected for sex 1610 / 256 9.8 (0.1-66), mean (range) The maturation of CL reaches 50% of adult values at 6 weeks after birth assuming a full-term gestational age of 40 weeks. Size-standardized CL reaches 95% of adult values at 2.5 yrs.
Long-Boyle (2015) One compartment popPK model. Allometric scaling for BW. CL corrected for maturation. 90 / NS 7 (0.1-24) CL (adjusted for BW) increases up through 12 yrs and then begins to decline to adult levels.
Neely (2016) One compartment popPK model. Allometric scaling for BW. CL and V corrected for age. 53 / NS 7.8 (0.2-19), mean (range) CL (adjusted for BW) increases up through ~7 yrs and then begins to decline to adult levels.
Marsit (2020) One compartment popPK model. Allometric scaling for BW. CL and V corrected for age. 136 / NS 6.6 (0.2-20.7), mean (range) Age was included as covariates on all parameters.
Poinsignon (2020) One compartment popPK model. Allometric scaling for BW. CL and V were corrected for maturation. 540 / 162 1.8 (0.02-24.1), mean (range) All parameters were corrected for maturation.
Ben Hassine (2021) Two compartment popPK model. Postmenstrual age dependent allometric scaling of BW on CL. CL corrected for day of therapy, GSTA1 diplotypes and regimen including fludarabine. 302 / NS 5.2 (0.1-20.1) CL was corrected for maturation.

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
Tran (2004) One compartment popPK model 20 / 1 5.5 (0.8-14.9) CL (mL/min/kg) was higher in children <6 years than in patients >6 years.
Oechtering (2005) One compartment popPK model 19 / 1 4 (0.9-17.3) No effect of age on exposure.
Zwaveling (2006) One compartment PK model 18 / 1 7.0 (0.5-16) CL (L/h/kg) proved to be dependent on age, whereas CL (L/h/m2) was age-independent.
Schechter (2007) One compartment popPK model 45 / 13 3.0 (0.25-16.2) CL (mL/min/kg) was significantly higher in children <4 yrs. However, CL (mL/min/m2) was significantly lower in children <1 yrs and <4 yrs. V (L/kg) was significantly higher in children <1 year or <4 years.
Nath (2008) One compartment PK model 40 / 7 3.2 (1.5-9.1) Age correlated with CL (L/h) and CL (L/h/kg), but not with CL (L/h/m2). AUC did not correlate with age.
Trame (2011) One compartment popPK model. Allometric scaling for BW. 94 / NS 9.2 (0.4-18.8) Effect of age was not described.
Veal (2012) One compartment popPK model. Allometric scaling for BW. 38 / NS 3.6 (0.7-13.1), mean (range) for iv subgroup Effect of age was not described.
McCune (2013) Non-compartmental pharmacokinetics, one or two compartment PK model. Allometric scaling for BW. 729 / NS 5.0 (0.1-20.0) Non-linear relationship between age and CL (mL/min/kg).
Diestelhorst (2014) One compartment popPK model. Allometric scaling for BW. 82 / NS NS (0.4-18.8) Effect of age was not described.
Okamoto (2014) One compartment popPK model. BW was included as covariate on CL and V. 25 / 5 6 (0.4-17) Effect of age was not described.
Nava (2018) One compartment popPK model. Allometric scaling for BW. CL corrected for maturation and GSTA1 diplotypes 112 / 20 5.4 (0.1-20) CL was corrected for maturation.
Alsultan (2020) One compartment popPK model. Allometric scaling for BW. 59 / NS 6.1 (0.16-13), mean (range) Effect of age was not described.
Yuan (2021) One compartment popPK model. CL corrected for BSA, GSTA1 diplotypes and ASAT. V corrected for BSA. 69 / NS 4.90 (0.50-15.18) No effect of age after including BSA as covariate.

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
Dalle (2003) Non-compartmental pharmacokinetics 14 / 14 0.4 (0.06-1) Cumulative dose of 16 mg/kg leads to increased exposure in infants compared to adults. No correlation between age and AUC in the complete cohort. A trend for correlation between age and AUC in the female subgroup was seen.
Kletzel (2006) Non-compartmental pharmacokinetics 30 / 8 8 (0.11-16) Effect of age was not studied.
Kim (2009) Non-compartmental pharmacokinetics 21 / NS 8 (0.25-18), mean (range) CL (mL/min/kg) was significantly higher in children <4 yrs.
Wall (2009) Non-compartmental pharmacokinetics 24 / 3 3.3 (0.5-16.7) No effect of age on CL (mL/min/kg).
Le Gall (2013) Non-compartmental pharmacokinetics 49 / 3 7.4 (0.2-18.4), mean (range) CL (mL/min/kg) was significantly higher in children <4 yrs.
Neroutsos (2021) Non-compartmental pharmacokinetics 76 / NS (12 <2 years) 6.5 (0.5-19) Effect of age was not studied.