CYP3A5 genotype-based model to predict tacrolimus dosage in the early postoperative period after living donor liver transplantation

Figures & data

Table 1 Characteristics of the study population

Characteristics	Mean ± SD (range)
Age (years)	49.2±8.7 (19–65)
Male, n (%)	46 (79.3)
Graft-to-recipient body weight ratio (%)	1.07±0.24 (0.59–1.60)
Hematocrit (%)	26.7±4.5 (15.8–40.9)
Total bilirubin (mg/dL)	2.4±1.9 (0.4–12.0)
ALT (iU/L)	141±113 (7–570)
Albumin (g/dL)	3.0±0.3 (1.7–3.9)
Tacrolimus dosage (mg/dose)	1.9±1.2 (0.1–6)
Body weight (kg)	61.4±10.1 (40.1–85.5)
Number of blood samples/patient	10.4±2.5 (3–13)
Tacrolimus concentration (ng/mL)	9.7±3.9 (1.6–21.4)

Abbreviation: ALT, alanine transaminase.

Figure 1 estimated clearance according to the CYP3A5 genotypes of the recipient and donor.

Notes: (A) On the first day after transplantation. (B) From day 1 to 14.
Abbreviations: POD, postoperative day; REDE, CYP3A5 expresser recipient and expresser donor; REDN, expresser recipient and nonexpresser donor; RNDE, nonexpresser recipient and expresser donor; RNDN, nonexpresser recipient and nonexpresser donor.

Figure 2 estimated volume of distribution from day 1 to 14.

Abbreviation: POD, postoperative day.

Table 2 Population pharmacokinetic parameters

Parameter	Mean	RSE (%)	Bootstrap (5th–95th percentile)
CL/F (L/h)	6.33	16	4.48–8.06
POD on CL/F	0.257	30	0.141–0.411
CYP3A5genotype	2.314 (REDE)	12	1.907–2.742 (REDE)
	1.523 (REDN)	32	1.201–1.923 (REDN)
V/F (L)	465	11	384–560
POD on V/F	0.322	16	0.233–0.409
ka(h^−1)	4.48 (fixed)	–	–
ω^2 C1/F	0.117 (IIV 34.2%)	23	0.071–0.160
ω^2 V/F	0.207 (IIV 45.5%)	23	0.139–0.289
σ^2 proportional error	0.182 (42.7%)	9	0.151–0.203
σ^2 additive error	0.838	22	0.509–1.156

Abbreviations: CL/F, clearance; POD, postoperative day; REDE, CYP3A5 expresser recipient grafted from CYP3A5 expresser donor; REDN, CYP3A5 expresser recipient grafted from CYP3A5 nonexpresser donor; RSE, relative standard error; V/F, volume of distribution; k_a, absorption rate constant; σ²ance of the residual error; ω², variance of the interindividual variability.

Figure 3 Goodness-of-fit plot.

Notes: (A) Observed vs IPRED of the base model. (B) Observed vs IPRED of the final model. (C) PRED vs CWRES. (D) Time vs CWRES.
Abbreviations: CWRES, conditional-weighted residuals; IPRED, individual predictive value; PRED, predictive value.

Figure 4 Visual predictive check plot.

Notes: The observed concentrations are shown as circles. The solid line and two dashed lines represent the 50th, 5th, and 95th percentiles of the observations. The red shaded area represents 90% CI of the simulation median, whereas the blue shaded areas represent 90% CI of the simulation 5th and 95th percentiles.

Table 3 Dosage suggestion in mg for tacrolimus from POD 1 to 14

	POD1	2	3	4	5	6	7	8	9	10	11	12	13	14
Target 10 ng/mL
REDE	2	2.5	3	3	3	3.5	3.5	3.5	3.5	3.5	4	4	4	4
REDN	1.5	1.5	1.5	2	2	2	2	2	2.5	2.5	2.5	2.5	2.5	2.5
Others	1	1	1	1	1	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Target 15 ng/mL
REDE	3	4	4	4.5	4.5	5	5	5.5	5.5	5.5	5.5	6	6	6
REDN	2	2.5	2.5	3	3	3	3	3.5	3.5	3.5	3.5	3.5	3.5	3.5
Others	1.5	1.5	1.5	1.5	2	2	2	2	2	2	2.5	2.5	2.5	2.5

Abbreviations: POD, postoperative day; REDE, CYP3A5 expresser recipient grafted from CYP3A5 expresser donor; REDN, CYP3A5 expresser recipient grafted from CYP3A5 nonexpresser donor.