. 2015 Jun 26;80(3):548–559. doi: 10.1111/bcp.12703

Table 2.

(Weight-corrected) midazolam systemic and apparent oral clearance, (weight-corrected) tacrolimus dose requirements, dose-corrected tacrolimus initial concentration (C₀) and area under the plasma concentration–time curve from 0 to 12 h (AUC_0–12), and (weight-corrected) tacrolimus steady-state clearance (CL) over time

	D7	M1	M3	M6	M12	Pvalue
MDZ IV CL (ml min^–1)
All	494 ± 204 (n = 35)^a	369 ± 135 (n = 28)^b	373 ± 141 (n = 64)^b	341 ± 134 (n = 21)^b	341 ± 125 (n = 46)^b	<0.001
CsA^†	290 ± 98 (n = 6)^a	250 ± 77 (n = 5)^a	255 ± 58 (n = 7)^a	241 ± 83 (n = 5)^a	279 ± 87 (n = 9)^a	0.843
Tac^†	535 ± 196 (n = 29)^a	395 ± 131 (n = 23)^b	388 ± 142 (n = 57)^b	373 ± 133 (n = 16)^b	356 ± 129 (n = 37)^b	<0.001
Tac CYP3A51/3	460 ± 258 (n = 5)^a	274 ± 125 (n = 3)^a	389 ± 190 (n = 0)^a	262 ± 39 (n = 2)^a	368 ± 108 (n = 9)^a	0.120
Tac CYP3A53/3^†	552 ± 184 (n = 24)^a	413 ± 125 (n = 20)^b	388 ± 132 (n = 47)^b	388 ± 135 (n = 14)^b	352 ± 137 (n = 28)^b	<0.001
MDZ IV Cl/weight (ml min^–1 kg^–1)
All	7.1 ± 3.2 (n = 35)^a	5.5 ± 2.5 (n = 28)^b	5.3 ± 2.1 (n = 64)^b	4.9 ± 2.1 (n = 21)^b	4.7 ± 1.6 (n = 46)^b	<0.001
CsA^†	4.1 ± 1.7 (n = 6)^a	3.4 ± 1.0 (n = 5)^a	3.5 ± 1.2 (n = 7)^a	3.2 ± 1.3 (n = 5)^a	4.2 ± 2.0 (n = 9)^a	0.863
Tac^†	7.7 ± 3.1 (n = 29)^a	5.9 ± 2.2 (n = 23)^b	5.5 ± 2.1 (n = 57)^b	5.5 ± 2.0 (n = 16)^b	4.7 ± 1.5 (n = 37)^b	<0.001
Tac CYP3A51/3	6.7 ± 4.4 (n = 5)^a	4.6 ± 2.7 (n = 3)^a	5.6 ± 2.8 (n = 10)^a	4.5 ± 1.4 (n = 2)^a	5.4 ± 1.5 (n = 9)^a	0.127
Tac CYP3A53/3^†	7.9 ± 2.9 (n = 24)^a	6.1 ± 2.1 (n = 20)^b	5.5 ± 1.9 (n = 47)^b	5.6 ± 2.1 (n = 14)^b	4.7 ± 1.1 (n = 28)^b	<0.001
MDZ PO Cl/F (ml min^–1)
All	924 ± 443 (n=35)^a	730 ± 344 (n=29)^b	685 ± 285 (n=66)^b	611 ± 324 (n=22)^b	694 ± 323 (n=50)^b	<0.001
CsA^†	579 ± 227 (n = 6)^a	505 ±171 (n = 6)^a	404 ± 89 (n = 7)^a	431 ± 151 (n = 5)^a	531 ± 240 (n = 10)^a	0.605
Tac All^†	996 ± 445 (n = 29)^a	789 ± 356 (n = 23)^b	719 ± 282 (n = 59)^b	664 ± 345 (n = 17)^b	735 ± 331 (n = 40)^b	<0.001
Tac CYP3A51/3	833 ± 494 (n = 5)^a	473 ± 305 (n = 3)^a	707 ± 332 (n = 10)^a	344 ± 35 (n = 2)^a	797 ± 266 (n = 10)^a	0.183
Tac CYP3A53/3^†	1031 ± 438 (n = 24)^a	836 ± 344 (n = 20)^b	721 ± 274 (n = 49)^b	708 ± 344 (n = 15)^b	715 ± 351 (n = 30)^b	0.001
MDZ PO Cl/F/weight (ml min^–1 kg^–1)
All	13.2 ± 6.5 (n = 35)^a	10.7 ± 5.2 (n =2 9)^b	9.8 ± 4.4 (n = 66)^b	8.6 ± 4.4 (n = 22)^b	9.7 ± 4.3 (n = 50)^b	<0.001
CsA^†	8.5 ± 4.2 (n = 6)^a	7.0 ± 2.2 (n = 6)^a	5.6 ± 1.9 (n = 7)^a	5.8 ± 2.3 (n = 5)^a	8.1 ± 5.3 (n = 10)^a	0.584
Tac All^‡	14.1 ± 6.6 (n = 29)^a	11.7 ± 5.3 (n = 23)^b	10.3 ± 4.4 (n = 59)^b	9.5 ± 4.5 (n = 17)^b	10.1 ± 3.9 (n = 40)^b	0.001
Tac CYP3A51/3	12.3 ± 8.6 (n = 5)^a	8.0 ± 6.2 (n = 3)^a	10.1 ± 5.1 (n = 10)^a	5.8 ± 2.0 (n = 2)^a	11.6 ± 3.7 (n = 10)^a	0.314
Tac CYP3A53/3^‡	14.5 ± 6.2 (n = 24)^a	12.3 ± 5.1 (n = 20)^b	10.4 ± 4.3 (n = 49)^b	10.0 ± 5.0 (n = 15)^b	9.6 ± 3.9 (n = 30)^b	<0.001
Tac C₀ (ng ml^–1)
Tac All	12.5 ± 3.7 (n = 29)^a	13.0 ± 3.3 (n = 23)^a	12.5 ± 2.9 (n = 59)^a	11.9 ± 3.3 (n= 1 7)^a	11.3 ± 3.1 (n = 40)^a	0.223
Tac CYP3A51/3^§	10.9 ± 3.2 (n = 5 )^a	14.2 ± 7.5 (n = 3)^a	11.6 ± 2.3 (n = 10)^a	13.8 ± 4.4 (n = 2)^a	11.4 ± 2.7 (n = 10)^a	0.657
Tac CYP3A53/3^§	12.9 ± 3.7 (n = 24)^a	12.8 ± 2.6 (n = 20)^a	12.6 ± 2.6 (n = 49)^a	11.6 ± 3.1 (n = 15)^a	11.2 ± 3.2 (n = 30)^a	0.152
Tac AUC_0–12 (ng h ml^–1)
Tac All	248 ± 70 (n = 29)^a	259 ± 59 (n = 23)^a	250 ± 53 (n = 59)^a	234 ± 116 (n = 17)^a	225 ± 54 (n = 40)^a	0.105
Tac CYP3A51/3^§	252 ± 76 (n = 5)^a	255 ± 54 (n = 3)^a	248 ± 55 (n = 10)^a	230 ± 59 (n = 2)^a	222 ± 57 (n = 10)^a	0.561
Tac CYP3A53/3^§	231 ± 35 (n = 24)^a	289 ± 96 (n = 2 0)^a	259 ± 47 (n = 49)^a	266 ± 97 (n = 15)^a	232 ± 43 (n = 30)^a	0.169
Tac dose (mg day^–1)
Tac All	12.5 ± 5.5 (n = 29)^a	10.9 ± 4.4 (n = 23)^b	9.8 ± 4.8 (n = 59)^c	7.6 ± 2.5 (n = 17)^de	7.3 ± 4.2 (n = 40)^e	<0.001
Tac CY¨3A51/3^§	17.0 ± 5.3 (n = 5)^a	11.5 ± 2.2 (n = 3)^ab	15.8 ± 3.8 (n = 10)^ab	10.5 ± 0.7 (n = 2)^ab	13.2 ± 3.7 (n = 10)^b	0.031
Tac CYP3A53/3^§	11.6 ± 5.2 (n = 24)^a	10.8 ± 4.7 (n = 20)^a	8.6 ± 4.1 (n = 49)^b	7.3 ± 2.4 (n = 15)^c	5.4 ± 2.0 (n = 30)^c	<0.001
Tac dose/weight (mg kg^–1 day^–1)
Tac All	0.18 ± 0.07 (n = 29)^a	0.16 ± 0.06 (n = 23)^ab	0.14 ± 0.08 (n = 59)^b	0.11 ± 0.05 (n = 17)^c	0.10 ± 0.06 (n = 40)^d	<0.001
Tac CYP3A51/3^§	0.24 ± 0.06 (n = 5)^a	0.19 ± 0.07 (n = 3)^a	0.23 ± 0.08 (n = 10)^a	0.19 ± 0.10 (n = 2)^a	0.19 ± 0.05 (n = 10)^a	0.052
Tac CYP3A53/3^§	0.16 ± 0.07 (n = 24)^a	0.15 ± 0.06 (n = 20)^a	0.12 ± 0.06 (n = 49)^b	0.10 ± 0.03 (n = 15)^c	0.07 ± 0.02 (n = 30)^c	<0.001
Tac C₀/dose (ng ml^–1 mg^–1)
Tac All	1.30 ± 0.88 (n = 29)^a	1.44 ± 0.89 (n = 23)^a	1.65 ± 1.07 (n = 59)^a	1.71 ± 0.82 (n = 17)^ab	1.95 ± 1.06 (n = 40)^b	0.003
Tac CYP3A51/3^§	0.72 ± 0.31 (n = 5)^a	1.14 ± 0.56 (n = 3)^a	0.77 ± 0.24 (n = 10)^a	1.24 ± 0.24 (n = 2)^a	0.90 ± 0.23 (n = 10)^a	0.145
Tac CYP3A53/3^§	1.42 ± 0.92 (n = 24)^a	1.49 ± 0.94 (n = 20)^a	1.83 ± 1.10 (n = 49)^a	1.77 ± 0.85 (n = 15)^a	2.30 ± 1.00 (n = 30)^b	0.001
Tac AUC_0–12/dose (ng h ml^–1 mg^–1)
Tac	47.0 ± 23.9 (n = 29)^a	54.7 ± 30.9 (n = 23)^ab	61.3 ± 33.3 (n = 59)^b	64.1 ± 18.7 (n = 17)^b	75.5 ± 37.2 (n = 40)^c	<0.001
Tac CYP3A51/3^§	29.6 ± 7.8 (n = 5)^a	43.9 ± 10.5 (n = 3)^ab	34.0 ± 9.3 (n = 10)^ab	47.6 ± 11.6 (n = 2)^b	37.4 ± 10.8 (n = 10)^ab	0.043
Tac CYP3A53/3^§	50.6 ± 24.6 (n = 24)^a	56.4 ± 32.9 (n = 20)^ab	67.0 ± 33.7 (n = 49)^bc	66.3 ± 18.7 (n = 15)^bc	88.2 ± 34.1 (n = 30)^c	<0.001

Abbreviations are as follows: All, all patients; CsA, cyclosporine-treated patients; MDZ IV CL. systemic midazolam clearance; MDZ IV CL/weight, weight-corrected systemic midazolam clearance; MDZ PO CL/F, apparent oral midazolam clearance; MDZ PO CL/F/weight, weight-corrected apparent oral midazolam clearance; Tac All, all tacrolimus-treated patients; Tac AUC_0–12, tacrolimus dose-interval area under the concentration–time curve; Tac AUC_0–12/dose, dose-corrected tacrolimus dose-interval area under the concentration–time curve; Tac C₀, tacrolimus predose trough level; Tac CL_ss, tacrolimus steady-state clearance; Tac CL_ss/weight, weight-corrected tacrolimus steady-state clearance; Tac dose, tacrolimus daily dose-requirements; Tac dose/weight, weight-corrected tacrolimus daily dose requirements; Tac C₀/dose, dose-corrected tacrolimus predose trough level; Tac CYP3A5*1/*3, tacrolimus-treated patients expressing CYP3A5; Tac CYP3A5*3/*3, tacrolimus-treated patients not expressing CYP3A5;

^†

P < 0.01;

^‡

P < 0.05 for CsA vs. Tac all and for CsA vs. Tac CYP3A5*3/*3.

^§

P < 0.0001 for Tac CYP3A5*1/*3 vs. Tac CYP3A5*3/*3.

Common superscripts ‘value^abc…’ indicate the absence of a statistical significant difference between values at different time points, whereas values without common superscripts are statistically significantly different, with an adjusted P value < 0.05 (Tukey–Kramer). P, P value for evolution over time.