Table 2.
Summary of population PK models of busulfan.
| References | N malignancy /N total | Age range (years) | Busulfan dosing | Structural model | Tested covariates | Included covariates | Final CL equation | Target daily exposure (AUC in mg.h/L) | Recommended initial dose |
|---|---|---|---|---|---|---|---|---|---|
| Model-informed dosing studies based on population PK models | |||||||||
| Bartelink et al. (80, 81) | Model development: 114/245 Model validation: 39/158 |
0.1–35 | IV q6 h, q12 h and q24 h | 2 compartment model Linear elimination parameters |
ABW, BSA, age, Supportive care treatments, baseline biological variables, diagnosis (malignancy vs. non-malignancy), dosing day | ABW for CL and Vd Dosing day for CL |
CLi = 3.32 (L/h) × (BW/ 15.3 kg)1.57×BW(−0.224) × Fday2−4 |
Target AUC: 22.5 Target window: 19.5–25.3 |
Bodyweight-based nomogram (80) |
| Ben Hassine et al. (82) | Model development: 191/302 Model validation: 67/100 |
0.1–20.1 | IV q6 h, q12 h and q24 h | 2 compartment model Linear elimination |
ABW, age, sex, diagnosis (malignant vs. non-malignant), Fludarabine co-administration, the day of conditioning, GSTA1 haplotypes, GSTA1 metabolic capacity (three groups based on promoter haplotypes), Transplantation centre, treatment number. |
ABW, PMA, the 1st day of conditioning, Fludarabine co-administration, and GSTA1 metabolic capacity for CL. ABW for Vd |
CLi = 4.92(L/h) × (BW/20kg)1.14×PMA(−0.20) × Fday1 × FGSTA1 × FFludarabine | Target AUC: 19.7 Target window: 14.8–24.6 |
Dose (mg) = AUCtarget × 4.92 (L/h) × (BW/20kg)1.14×PMA(−0.20) × Fday1 × FGSTA1 × FFludarabine |
| Booth et al. (63) | 15/24 | 0.3–16.7 | IV q6 h | 1 compartment, linear elimination | ABW, BSA, age | ABW for CL and Vd | CLi = 4.04 (L/h) × (ABW/20)0.742 | Target AUC: 18.5 Target window: 14.8–22.2 |
For q6 h: ≤ 12 kg: 1.1 mg/kg/dose >12 kg: 0.8 mg/kg/dose |
| Choi et al. (83) | 33/36 | 18–64 | IV q6 h | 1 compartment model with linear elimination | ABW, BSA, sex, drug interaction with azoles, AST, ALT, GSTA1, GSTM1, GSTT1, GSTP1 | ABW and GSTA1(*A/*A vs. *A/*B) for CL | CLi = 11.0 (L/h) × (BW/60 kg)0.843 × FGSTA1 | Target AUC: NA Target window: 15.6–24.6 |
NA |
| Diestelhorst et al. (84) | Model Building: NR/82 Model Validation: NR/24 |
0.1–18.9 | Model building: IV q6 h Model validation: IV q24 h |
1 compartment model with linear elimination | ABW, BSA, age, height, sex | ABW for CL BSA for Vd |
CLi = 3.04 (L/h) × (BW/16.1 kg)0.797 | Target AUC: 18.8 Target window: NS |
Dose (mg) = AUCtarget × 3.04 (L/h) × (BW/16.1kg)0.797 |
| Kawazoe et al. (85) | NR/54 | 0.3–53.5 | IV q6 h | 2 compartment model with linear elimination | Based on the model from McCune et al. (86) | CLi = 11.8 (L/h) × (NFMcl/70 kg)0.75 × Fmat × FT_CL | Target AUC: NR Target window: 14.8–24.6 |
Dose (mg) = 11.8 (L/h) × (NFMcl/70kg)0.75 × Fmat × FT_CL | |
| Langenhorst et al. (87) | 231/385 | 0.16–73 | IV | 2 compartment model with linear elimination | ABW, BSA, age, supportive care treatments, baseline biological variables, diagnosis (malignancy vs. non-malignancy), dosing day | ABW for CL and Vd Dosing day for CL |
CLi = 7.48 (L/h) × (BW/43 kg)1.03×BW(−0.138) × Fday2−4 | Target AUC: 22.5 Target window: 20.3–24.8 |
NA, only tested for TDM-guided cumulative exposure |
| Langenhorst et al. (87) | 231/385 | 0.1673 | IV | 2 compartment model with linear elimination and a theoretical compartment for theoretical glutathione depletion | Based on Bartelink et al. (80, 81) | Based on Bartelink et al. (80, 81) + Age for GSH depletion factor. |
CLi = 7.61 (L/h) × (BW/43 kg)1.04×BW(−0.14) | Target AUC: 22.5 Target window: 20.3–24.8 |
NA, only tested for TDM-guided cumulative exposure |
| Long-Boyle et al. (88) | Model development: NR/90 Model validation: NR/21 |
0.124 | IV q6 h | 1 compartment model with non-linear elimination | ABW, BSA, height, age, sex, baseline biological variables | ABW for CL and Vd Age-dependent maturation for CL |
<12 kg: CLi = 4.32 (L/h) × (BW/22 kg)0.75 × (1+ Sl < bp × age) ≥12 kg: CLi = 4.32 (L/h) × (BW/22 kg)0.75 × (1+ Sl<bp × Bp) × [1- Sl>bp × (age-12)] |
Target AUC: 18.0 Target window: 14.4–21.6 |
<12 kg: Dose (mg) = AUCtarget ×4.32 (L/h) × (BW/22 kg)0.75 × (1+ 0.032 × age) ≥12 kg: Dose (mg) = AUCtarget ×4.32 (L/h) × (BW/22 kg)0.75 × (1+ 0.032 ×12) × [1+0.0138 × (age-12)] |
| McCune et al. (86) | 978/1,481 | 0.1–65.8 | IV q6 h, q8 h, q12 h, and q24 h | 2 compartment model with linear elimination | ABW, height, post-menstrual age, age, sex, diagnosis (malignancy vs. non-malignancy), time since Bu treatment initiation | NFM (dependent of ABW, height and sex) for CL and Vd PMA-dependent maturation (Fmat) for CL Sex for Vd Time since Bu treatment initiation (FT_CL) |
CLi = 12.4 (L/h) × (NFMcl/70 kg)0.75 × Fmat × FT_CL | Target AUC: 18.5 Target window: 14.2–23.1 |
Dose (mg) = AUCtarget ×12.4 (L/h) × (NFMcl/70 kg)0.75 × Fmat |
| Nava et al. (89) | 52/112 | 0.1–20 | IV q6 h and q24 h | 1 compartment, linear elimination | ABW, age, sex, diagnosis (malignant vs. non-malignant), co-administered chemotherapy, GSTA1 metabolic capacity (three groups based on promoter haplotypes) | ABW and PMA-dependent maturation (Fmat) for CL GSTA1 metabolic capacity for CL PMA for Vd |
CLi = 13.7 (L/h) × (BW/70 kg)0.75 × Fmat × FGSTA1 | Target AUC: 18.5 Target window: 14.8–24.6 |
Dose (mg) = AUCtarget ×13.7 (L/h) × (BW/70 kg)0.75 × Fmat × FGSTA1 |
| Neely et al. (90) | Model building: NR/53 Model validation: NR/136 |
0.1–21 | IV q6 h | 1 compartment non-parametric model with linear elimination (estimated parameters are Ke and Vd) | ABW, IBW, age | IBW and age for Ke and Vd | CL = Ke/Vd Ke = KeS×IBW−0.25 × (0.51 + 0.10×Age - 0.01 × Age2 + 0.00029 × Age3) Vd = VS × IBW × (0.71−0.016 × Age + 0.0017 × Age2) |
Target AUC: 18.0 Target window: 14.4–21.6 |
For q6 h: ≤ 12 kg: 1.1 mg/kg >12 kg: 1.0 mg/kg |
| Nguyen et al. (57) | 15/24 | 0.45–16.7 | IV q6 h | 1 compartment model with linear elimination | Height, age, BSA, ABW | ABW for CL and Vd | CLi = 2.97 (L/h) + 4.57 × [LN(ABW-3)] | Target AUC: 18.5 Target window: 14.8–24.6 |
For q6 h: <9 kg: 1.0 mg/kg/dose ≥9 to <16 kg: 1.2 mg/kg/dose ≥16 to <23 kg: 1.1 mg/kg/dose ≥23 to <34 kg: 0.95 mg/kg/dose ≥34 kg: 0.8 mg/kg/dose |
| Paci et al. (66) | 82/115 | 0.1–15 | IV q6 h | 1 compartment model with linear elimination | ABW, BSA, age, sex, seizure prophylaxis, baseline biological variables | ABW for CL and Vd | <9 kg: CLi = 2.18 (L/h) × (BW/9 Kg)1.26 >9 kg: CLi = ×2.18 (L/h) × (BW/9 Kg)0.76 |
Target AUC: 19.7 Target window: 14.8–24.6 |
<9 kg: Dose (mg) = AUCtarget ×2.18 (L/h) × (BW/9 Kg)1.26 >9 kg: Dose (mg) = AUCtarget ×2.18 (L/h) × (BW/9 Kg)0.76 |
| Philippe et al. (91) | 84/163 | 0.17–21 | IV q6 h | 1 compartment non-parametric model with linear elimination (estimated parameters are Ke and Vd) | NA | IBW and age for Ke and Vd | CL = Ke/Vd Ke = KeS × IBW−0.25 × (0.51 + 0.10 × Age - 0.01 × Age2 + 0.00029 × Age3) Vd = VS × IBW × (0.71−0.016 × Age + 0.0017 × Age2) |
Target AUC: NA Target window: 14.8-24.6 |
Based on the highest cumulative probability of target interval attainment |
| Poinsignon et al. (92) | 140/540 (75% model development and 25% model validation) | 0.02–24.1 | IV q6 h | 1 compartment model with linear elimination | ABW, age | ABW and PMA-dependent maturation (Fmat) for CL and Vd | CLi = 2.90 (L/h) × (BW/12 kg)1.19×BW(−0.134) × Fmat | Target AUC: 19.7 Target window: 14.8–24.6 |
For q6h: ≤ 11 kg: 1.15 mg/kg/dose >11 to ≤ 17 kg: 1.25 mg/kg/dose >17 to ≤ 25 kg: 1.05 mg/kg/dose >25 to ≤ 40 kg: 0.9 mg/kg/dose >40 kg: 0.8 mg/kg/dose |
| Rhee et al. (93) | NR/137 (70.8 % acute leukaemia) | 0.6–22.2 | IV q24 h | 1 compartment model with linear elimination | ABW, BSA, age, height, sex, dosing day, baseline biological variables | BSA for CL and Vd | CLi = 10.7 (L/h) × (BSA/1.73)1.07 × (1-e(−0.693/0.326)×Age) × Fday × FAST | Target AUC: 18.75 Target window: 15.0–22.5 |
Age and BSA based nomogram [Rhee et al. (93)] |
| Savic et al. (67) | NR/149 | 0.1–3.3 | IV q6 h and q24 h | 1 compartment model with linear elimination | ABW, BSA, age, height, sex | ABW for CL and Vd Age-dependent maturation for CL | CLi = 2.3 (L/h) × (Matmag + (1 – Matmag) × [1 – e (−age × Kmat)] × (BW/8 kg)0.75 | Target AUC: 18.0 Target window: 14.4–21.6 |
Dose (mg) = AUCtarget × (0.46 + (1 – 0.46) × [1 – e (−age×1.4)] × (BW/8 kg)0.75 |
| Shukla et al. (94) | Model building: NR/299 Model validation: NR/59 |
Model building: NR Model validation:0.2–20 |
IV q6 h, q12 h, and q24 h | 1 compartment model with linear elimination | ABW, age, height, sex, dosing day, CloFluBu regimens | FFM based on ABW, height and sex for CL and Vd Age-dependent maturation for CL Day of conditioning CloFluBu regimens |
CLi = 3.96 (L/h) × (Matmag + (1 – Matmag) × [1 – e (−age×Kmat)] × (FFM/12 kg)0.75 × Fday1 × Fregimen | NA | Dose (mg) = AUCtarget ×3.96 (L/h) × (Matmag + (1 – Matmag) × [1 – e (−age×Kmat)] × (FFM/12 kg)0.75 × Fday1 × Fregimen |
| Trame et al. (95) BSA based | NR/94 | 0.1–18.8 | Oral q6 h IV q24 h |
1 compartment model with linear elimination | ABW, BSA, age | BSA for CL | CLi = 4.16 (L/h) × BSA | Target AUC: 18.8 Target window: 14.8–24.6 |
Dose (mg) = AUCtarget ×4.16 (L/h) × BSA |
| Trame et al. (95) weight based | NR/94 | 0.1–18.8 | Oral q6 h IV q24 h |
1 compartment model with linear elimination | ABW, BSA, age | ABW for CL | CLi = 4.11 (L/h) × (ABW/27.2)0.75 | Target AUC: 18.8 Target window: 14.8–24.6 |
Dose (mg) = AUCtarget ×4.11 (L/h) × (BW/27.2 kg)0.75 |
| Wu et al. (96) | 53/53 | 7.0–59.0 | IV q6 h | 1 compartment model with linear elimination | ABW, BMI, AIBW, BSA, sex, serum creatinine | BSA for CL and Vd | CL = 11.1 (L/h) × (BSA/1.587)0.955 | NA | Dose (mg) = AUCtarget ×11.1 (L/h) × (BSA/1.587)0.955 |
| Yuan et al. (97) | Model building: 26/69 Model validation: 4/14 |
0.5–15.2 | IV q6 h | 1 compartment model with linear elimination | BSA, AST, GSTA1 (*A/*A vs. *A/*B) | BSA for CL and Vd AST and GSTA1 for CL |
CL = 4.92 (L/h) × (BSA/0.67)0.83 × (AST/29.10)−0.21 × FGSTA1 | Target AUC: 18.5 Target window: 14.8–22.2 |
GSTA1-*A/*A: BSA 0.2–0.4 m2: 45 mg/m2 BSA 0.4–0.7 m2: 42 mg/m2 BSA 0.7–1.6 m2: 38 mg/m2 GSTA1-*A/*B: BSA 0.2–0.4 m2: 40 mg/m2 BSA 0.4–0.7 m2: 37 mg/m2 BSA 0.7–1.6 m2: 34 mg/m2 |
| Zwaveling et al. (98) | 35/77 | 0.2–23 | IV q6 h and q24 h | 1 compartment model with linear elimination | ABW, BSA, Age, diagnosis (malignant vs. non-malignant) GSTA1, GSTM1, GSTP1, GSTT1 |
ABW for CL and Vd | CLi = 4.8 (L/h) × (ABW/19)0.84 | NA | NA |
| Dosing recommendations not based on population PK studies | |||||||||
| Ansari et al. (38) | 75 | 0.1–20 | IV q6 h | NA | NA | NA | NA | Target window: 14.4–21.6 | For q6h: <3 months: 16 mg/m2/dose >3 months to <1 year: 0.8 mg/kg/dose >1 year old to <4 years old: 1 mg/kg/dose >4 years old: 0.8 mg/kg/dose |
| Buffery et al. (99) | 150 | 0.5–58 | Oral or IV q6 h IV q24 h |
NA | NA | NA | NA | Target window: 15.2–22.2 in children, 14.8–23.0 in adults | For q6h: 10–16 kg: 1.2 mg/kg/dose 17–18 kg: 1.1 mg/kg/dose 19–22 kg: 1 mg/kg/dose 23–25 kg: 0.9 mg/kg/dose >26 kg: 0.8 mg/kg/dose |
| Wall et al. (100) | 24 | 0.5–16.7 | IV q6 h | NA | NA | NA | NA | Target window: 14.8–22.2 | For q6h: <4 years: 1 mg/kg/dose ≥4 years: 0.8 mg/kg/dose |
ABW, actual body weight; AIBW, adjusted ideal body weight; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; BMI, body mass index; BSA, body surface area; Bu, busulfan; BW, body weight; CL, clearance; Cmax, maximum concentration; F, fraction absorbed (bioavailability); FFM, fat-free mass; GSTA1, glutathione S-transferase A1; i, intrinsic; IBW, ideal body weight; IV, intravenous; Ke, elimination rate constant; mag, magnitude; mat, maturation; LN, natural logarithm; NA: Not applicable; NFM, normal fat mass; NR, not reported; PMA, post-menstrual age; q12h, every 12 hours; q24h, every 24 hours; q6h, every 6 hours; q8h, every 8 hours; Vd, volume of distribution.