Predictive value of tacrolimus concentration/dose ratio in first post-transplant week for CYP3A5-polymorphism in kidney-transplant recipients

Table 1 Characteristics of patients (n = 86), mean ± SD

Characteristics		Values, range
Age (years)		36.13 ± 8.71 (18-63)
Gender, n (%)	Male	61 (70.9)
	Female	25 (29.1)
Donor type, n (%)	Living related	11 (12.8)
	Living unrelated	75 (87.2)
Causes of end-stage renal disease, n (%)	Chronic glomerulonephritis	83 (96.5)
	Pyelonephritis	3 (3.5)
HLA mismatch		3.38 ± 1.12 (1-6)
Height (cm)		163.76 ± 6.44 (145-176)
Weight (kg)		54.15 ± 8.38 (40-89)
BMI (kg/m2)		20.16 ± 2.71 (15.6-34.5)
Creatinine pre-transplantation (μmol/L) (n = 85)		847.46 ± 541.29 (375.00-5444.70)
Creatinine post-transplantation (μmol/L)
Day 1 (n = 80)		630.33 ± 191.09 (232.30-1216.15)
Day 2 (n = 86)		362.83 ± 159.12 (124.80-893.71)
Day 3 (n = 84)		179.59 ± 118.19 (68.60-653.88)
Day 4 (n = 83)		136.35 ± 82.07 (51.30-542.60)
Day 5 (n = 68)		125.38 ± 76.48 (59.90-499.02)
Day 6 (n = 69)		116.43 ± 66.98 (58.60-491.73)
Day 7 (n = 83)		104.67 ± 46.09 (53.50-337.06)
eGFR pre-transplantation (mL/minute) (n = 85)		8.70 ± 2.64 (1.15-18.88)
eGFR post-transplantation (mL/minute)
Day 1 (n = 80)		11.49 ± 4.19 (5.38-25.53)
Day 2 (n = 86)		21.16 ± 9.13 (8.23-61.43)
Day 3 (n = 84)		45.11 ± 16.57 (10.84-84.24)
Day 4 (n = 83)		55.83 ± 16.89 (13.07-103.74)
Day 5 (mL/minute) (n = 68)		60.06 ± 16.91 (14.77-109.33)
Day 6 (mL/minute) (n = 69)		63.39 ± 16.01 (14.42-102.14)
Day 7 (mL/minute) (n = 83)		69.13 ± 17.83 (25.15-141.30)
Delayed graft function, n (%)		1 (1.2)
Clinical acute rejection, n (%)	Yes	1 (1.2)
	No	85 (98.8)
CYP3A5, n (%)	CYP3A51/1	9 (10.5)
	CYP3A51/3	40 (46.5)
	CYP3A53/3	37 (43.0)

HLA: Human leucocyte antigen; BMI: Body mass index; eGFR: Estimated glomerular filtration rate.

Table 2 Comparisons of tacrolimus dose, C0 and dose-adjusted C0 between CYP3A5 fast metabolizers and slow metabolizers in renal transplant recipients

Parameters	CYP3A5 fast metabolizers	CYP3A5 slow metabolizers	P value
Dose (mg/day)
Initial dose (n = 86)	5.84 ± 0.72 (5.0-8.0)	6.00 ± 0.67 (5.0-8.0)	0.192
Adjusted dose (n = 86)	6.52 ± 1.18 (5.0-10.0)	6.08 ± 0.86 (4.0-8.0)	0.149
Dose (mg/kg/day)
Initial dose (n = 86)	0.11 ± 0.01 (0.09-0.14)	0.11 ± 0.01 (0.09-0.15)	0.236
Adjusted dose (n = 86)	0.12 ± 0.02 (0.09-0.19)	0.11 ± 0.02 (0.07 ± 0.16)	0.091
Co (ng/mL)
Day 1 (n = 85)	3.93 ± 2.38 (1.1-15.1)	6.66 ± 3.25 (1.5-15.5)	< 0.001
Day 2 (n = 84)	7.46 ± 3.93 (2.5-18.7)	11.88 ± 5.45 (4.2-30.1)	< 0.001
Day 3 (n = 84)	5.84 ± 3.07 (2.0-20.4)	9.68 ± 4.37 (2.1-21.5)	< 0.001
Day 4 (n = 76)	4.66 ± 2.19 (2.2-11.1)	8.70 ± 4.56 (2.2-20.0)	< 0.001
Day 5 (n = 55)	4.10 ± 1.68 (1.9-9.5)	8.39 ± 5.17 (1.2-24.5)	< 0.001
Day 6 (n = 64)	4.38 ± 4.72 (1.5-31.0)	7.72 ± 5.03 (1.7-26.5)	< 0.001
Day 7 (n = 81)	3.11 ± 1.11 (1.1-6.3)	6.32 ± 3.08 (2.7-17.4)	< 0.001
C0/D (ng/mL)/(mg/day)
Day 1 (n = 85)	0.68 ± 0.40 (0.18-2.52)	1.11 ± 0.50 (0.21-2.21)	< 0.001
Day 2 (n = 84)	1.31 ± 0.74 (0.40-3.74)	2.00 ± 0.93 (0.61-5.02)	< 0.001
Day 3 (n = 84)	1.02 ± 0.60 (0.40-4.08)	1.63 ± 0.78 (0.34-3.66)	< 0.001
Day 4 (n = 76)	0.82 ± 0.41 (0.30-1.98)	1.48 ± 0.83 (0.31-4.00)	< 0.001
Day 5 (n = 55)	0.72 ± 0.32 (0.30-1.66)	1.45 ± 1.00 (0.17-4.90)	< 0.001
Day 6 (n = 64)	0.76 ± 0.79 (0.30-5.17)	1.32 ± 0.98 (0.24-5.30)	< 0.001
Day 7 (n = 81)	0.54 ± 0.20 (0.22-1.05)	1.07 ± 0.59 (0.48-3.48)	< 0.001

C0/D: Concentration-to-dose.

Table 3 The sensitivity, specificity and cut-off points of concentration-to-dose ratio for the prediction of CYP3A5 polymorphism

Post-transplantation (days)	AUC	Cut-off	Sensitivity (%)	Specificity (%)
Day 1 (n = 85)	0.839	0.92	84.6	84.6
Day 2 (n = 84)	0.751	1.79	76.9	76.9
Day 3 (n = 84)	0.788	1.45	69.2	84.6
Day 4 (n = 76)	0.769	1.08	69.2	76.9
Day 5 (n = 55)	0.827	1.16	76.9	88.5
Day 6 (n = 64)	0.896	0.61	100.0	65.4
Day 7 (n = 81)	0.833	0.79	76.9	84.6

AUC: Area under the curve.