Table 3.

Summary of studies assessing busulfan pharmacogenetics and pharmacokinetics.

References	N ALL/N total	Age range (years)	Conditioning regimen(s)	Tested marker(s)	Tested Bu PK parameters in relation to the marker	PK findings	Clinical findings in relation to the biomarker
Abbasi et al. (105)	0/185 (48 AML patients)	0.5–66	IV Bu (N = 57): q12 h or q6 h Oral Bu (N = 128): q6 h Combinations with Cy, Flu, Thio, VP16, Mel	GSTA1 GSTM1	CL Dose adjustments	No association with IV Bu Decreased CL of oral Bu in GSTA1*B individuals	NA
Ansari et al. (106)	2/28	0.4–19.8	q6 h IV Bu with Cy	GSTA1 GSTP1 GSTM1	AUC Cmax Css CL	GSTM1-null genotype associated with: 1.2-fold higher AUC 1.3-fold higher Cmax 1.2-fold higher Css 1.3-fold lower CL	NA
Ansari et al. (107)	6/69	0.1–19.9	q6 h IV Bu: BuCy BuCyVP16 BuMel	GSTA1 GSTP1 GSTM1	Cmax AUC Css CL	Higher CL in presence of GSTA1-*A2 Lower CL with GSTM1-null in patients >4 years	Higher risk of SOS with GSTA1 homozygous and heterozygous *B1b (HR 10 and 5.6, respectively) 4-fold higher risk of aGVHD with GSTM1-null in patients >4 years
Ansari et al. (108)	0/44 (only thalassaemic patients)	1.5–17	q6 h IV Bu with Cy	GSTA1 GSTM1	Css Cmax AUC CL	Higher CL in presence of GSTA1-*A Higher Bu exposure and lower clearance in GSTA1-*B/*B patients (p ≤ 0.01)	5-fold higher risk of aGVHD and TRT with GSTM1-null
Ansari et al. (39)	12/138	0.1–9.9	q6 h IV Bu with other agents (Cy, Mel, VP16)	GSTA1 GSTM1 GSTP1	Cmax Css AUCcum CL Initial/adjusted dose ratio	Higher CL and lower AUCcum with GSTA1 diplotypes associated with rapid metabolising capacity Lower CL and higher AUCcum with GSTA1 diplotypes associated with slow metabolising capacity Lower CL in patients >4 years with GSTM1-null	Higher incidence of SOS, aGvHD and combined TRT, with GSTA1 diplotypes with slow metabolising capacity GSTP1 313GG associated with acute GvHD grade I–IV GSTM1-non-null genotype associated with HC
Ben Hassine et al. (82)	44/402 (302 for model building, 100 for model validation)	0.1– 20.1	q24 h, q12 h, q6 h IV Bu with other agents	GSTA1	CL Vd	GSTA1-G3 (slow metabolising capacity) associated with 12% lower CL GSTA1-G1 (rapid metabolising capacity) associated with 10% higher CL	NA
Bonifazi et al. (109)	35/185 patients received Bu	18–59	q6 h IV Bu with Cy or Flu	30 genes including GSTA1 GSTM1 GSTT1 GSTA2	AUC	1.5-fold higher AUC in GSTA2 S112T serine/serine patients compared to threonine amino acid substitution patients	NA
Bremer et al. (110)	13/114	16–65	q6h IV Bu with Cy	GSTA1 GSTT1 GSTM1 GSTP1	CL/F Css	CL/F 11% and 18% lower when 1 or 2 GSTA1-*B alleles are present, respectively. 60% higher Css with GSTA1-*B/*B and GSTT1/GSTM1 double-null	Higher mortality within the first 30 days post-HSCT with GSTM1-null
Choi et al. (83)	13/36	18–64	q6 h or q24 h IV Bu with Cy or Flu	GSTA1 GSTT1 GSTM1 GSTP1	CL AUC	15% lower CL in heterozygous GSTA1-*B	NA
Elhasid et al. (111)	0/18 (only congenital haemoglobinopathies)	0.8–16	Oral Bu q6h	GSTA1 GSTT1 GSTM1 GSTP1	Cmax AUC AUC/kg CL/F T1/2 Vd/F Cmax/AUC ratio	Association between GSTA1 and GSTP1 genotypes with Cmax and AUC	Association between GSTM1-null genotype with acute/chronic GvHD and with graft rejection
Gaziev et al. (112)	0/71 (only thalassaemic patients)	1.6–27	q6 h IV Bu with Cy or Thio	GSTA1 GSTT1 GSTM1 GSTP1	Css AUC CL T1/2	10% lower CL in patients carrying GSTA1*B	NA
Johnson et al. (113)	2/29	0.1–18.3	q6 h or q12 h IV Bu with Cy or Flu	GSTA1 GSTM1 GSTP1	CL AUC Css Cmax	30% lower CL with GSTA1-*B or *B/*B Significant differences in AUC, Css and Cmax between GSTA1-*A/*A, *A/*B and *B/*B genotypes (lower exposures with *A/*A and higher exposures with *B/*B)	NA
Kim et al. (114)	6/58	16–58	q6 h IV Bu alone or with Cy or Flu	GSTA1 GSTT1 GSTM1	CL AUC	Higher AUCs with GSTA1-*A Lower Bu CL in GSTM1/GSTT1-double-null patients	NA
Lee et al. (71)	7/24	0.9–18.1	q24 h IV Bu with Flu. VP16 was added for ALL patients	GSTA1 GSTT1 GSTM1	AUC first-day CL Dose modification	NS Tendency of higher AUC in carriers of GSTA1-*A/*B genotype or GSTT1-null genotype	NA
Nava et al. (102)	10/101	0.1–21.0	q6 h IV Bu-based conditioning: BuCy BuFlu BuCyVP16 BuMel	GSTA1	CL AUC	GSTA1-diplotype-based metabolic groups associated with the mean prediction error of CL CyGSTA1 slow metabolising capacity associated with AUCs within therapeutic window GSTA1 rapid metabolising capacity associated with subtherapeutic AUCs	NA
Nava et al. (89)	8/112	0.1–20.0	q6 h and q24 h IV Bu-based conditioning: BuCy BuCyVP16 BuMel BuCyMel BuMelAraC	GSTA1	CL Vd AUC first-dose	GSTA1-G3 (slow metabolising capacity) associated with 11% lower CL GSTA1-G1 (rapid metabolising capacity) associated with 7% higher CL Doses considering GSTA1 resulted in no G1 patients outside the target AUC	NA
Nishikawa et al. (115)	0/20 (9 AML patients)	0.5–17	q6 h IV Bu with other agents (Cy, Flu, Mel, VP16)	GSTA1 GSTT1 GSTM1	CL AUC Ke	Poor metabolizers, defined as patients carrying ≥1 GSTA1-*B or GSTM1-double-null genotypes, had lower 28%, lower CL and 52% higher AUC than extensive metabolizers	NA
Srivastava et al. (116)	0/114 (only thalassaemic patients)	2–16	q6 h oral Bu with Cy	GSTM1 GSTT1	CL/F Css	Lower Bu CL/F with GSTM1-null	3-fold higher risk of SOS with GSTM1-null
ten Brink et al. (117)	NR/84 (31 patients with haematological malignancies including ALL)	Mean 6.1 years (± 5.4 SD)	q24 h IV Bu with Cy or Flu and other agents (Cy or Flu, Thio, Mel, VP16, Clo)	GSTA1 ABCB4 CYP39A1 CYP2C19 SLC7A8 SLC22A4	CL AUC	8% lower CL with GSTA1-*A/*B and 26% lower CL with GSTA1-*B/*B compared to wild-type (*A/*A), with a larger effect of GSTA1 in patients <2 years of age 13% lower CL With heterozygous CYP39A1 variant and 17% lower clearance with homozygous mutant CYP39A1 39% lower CL with homozygous carriers for both haplotypes of GSTA1 and CYP39A1	NA
Uppugunduri et al. (118)	6/66	0.1–19.9	q6 h IV Bu-based conditioning: BuCy BuFlu BuCyVP16 BuMel	CYP2C9 CYP2C19 CYP2B6 FMO3	Bu/sulfolane metabolic ratio	Higher metabolic ratio in CYP2C9*2 and *3 (decreased function) allele carriers Lower metabolic ratio in CYP2C19*17 (increased function) allele carriers	Higher metabolic ratio (<5) associated with lower graft failure risk Higher incidence of relapse and graft failure in patients with malignant disease with homozygous reduced-function CYP2B6 alleles
Yin et al. (119)	8/25	13–61	q6 h IV Bu with other agents (Cy, Flu, Mel, VP16, AraC, Decitabine, Semustine)	GSTA1 GSTP1	AUC CL Cmax T1/2 Vd	Lower CL and higher exposure in GSTA1-*A/*B patients compared with *A/*A patients Higher CL in presence of GSTP1 313A-*G (dominant allele)	NS
Yuan et al. (97)	5/69 (model building) + R/14 (model validation)	0.5–15.8	q6 h IV Bu with other agents (Cy, Flu, Mel, VP16, AraC, decitabine, semustine)	GSTA1	CL AUC0−6h	17% lower CL in heterozygous GSTA1-*B	Worse neutrophil recovery and lower survival in heterozygous GSTA1-*B patients
Zwaveling et al. (98)	NR/77 (35 patients with malignancies)	0.2–23	q24 h or q6 h IV Bu with other agents (Cy, Mel, Flu, VP16)	GSTA1 GSTT1 GSTM1 GSTP1	CL	NS	1.7-fold higher risk of SOS in GSTM1-null patients (trend, p = 0.07)

ALL, acute lymphoblastic leukaemia; AML, acute lymphoblastic leukaemia; AUC, area under the curve; AUC_cum, cumulative area under the curve; Bu, busulfan; CL, clearance; C_max, maximum concentration; Css, steady state concentration; Cy, cyclophosphamide; F, fraction absorbed (bioavailability); Flu, fludarabine; GSTA1, glutathione S-transferase A1; GvHD, graft-versus-host disease; HC, haemorrhagic cystitis; HR, hazard ratio; IV, intravenous; K_e, elimination rate constant; Mel, melphalan; NS, not significant; NR, not reported; q12h, every 12 hours; q24h, every 24 hours; q6h, every 6 hours; q8h, every 8 hours; SOS, sinusoidal obstruction syndrome; T_1/2, half-life; Thio, thiotepa; TRT, treatment-related toxicity; V_d, volume of distribution; VP16, etoposide.