Study Of Classic And Population Pharmacokinetics For Tacrolimus In Chinese Recipients Of Liver Transplantation

Objective: To evaluate the classic and population pharmacokineticscharacter of tacrolimus (TAC) orally administered from routing therapeutic drugmonitoring in liver transplant recipients for improving the schedule of indiviaualdosage.Method:1. 22 recipients after liver transplantation were given tacrolimus-basedimmunosurpressive regimen 24 hours after surgery. To determine TAC levelsblood samples were drawn from vein into EDTA tube at 0, 0.33, 0.66, 1, 1.5, 2, 3,4, 6, 8, 10, 12h. The whole blood concentration was measured by MEIA. Thepharmacokinetic parameters were calculated and the C-T curves were depicted byPKBP-N1 program.2. TAC whole concentration data in 22 recipients and TAC troughconcentration data in 151 recipients were estimated by nonlinear mixed effectmodel (NONMEM) program. The effect of gender (GEN), age (AGE), bodyweight (BW), post of operation days (POD), dosage (DOSE), concurrent use ofdrug, liver function, kidney function, and hematocrit (HCT) on pharmacokineticparameters were evaluated with structural parameter models.Results:1. The C-T curves showed two-compartment open model ofpharmacokinetics in the steady state after oral tacrolimus. The pharmacokineticparameters of TAC for 22 patients were as follows respectively: t_max=0.66～2h,C_max=15.1～40μg/L, t_1/2a=1.22±2.10h, h_1/2β=21.04±10.11h, K_a=2.18±0.91/h, CL_s=0.56±0.34 L/(h.kg), AUC_0～12=136.19±33.68μg.h/L. There were relativegood relation between C_min and AUC_0～12 (r=0.82), whereas the better relation isrepectively between C₃ and AUC_0～12(r=0.95), between C₄ and AUC_0～12(r-0.94).The 2-hour concentration could predict the 98% AUC with C_0.66 and C₆, C₁ and C₆,C₂ and C₈ respectively. The 3-hour concentration could predict the total AUC_0～12reasonably well (r=0.99). From stepwise multiple regression, the abbreviatedAUC at C₀, C_0.33, C_0.66 or C₀, C_0.66, C₃ and C_0.33, C₂, C₈ hours could predict thetotal AUC_0～12 most accurately.2. Two-compartment model fitted was better than one-compartment model inroutine monitoring steady-state through concentration of TAC. The final modeland parameters of 22 patients data set were: population standard value CL was0.010KL/h, V2 was 0.086KL, Q was 0.037KL/h, V3 was 0.351 KL, KA was2.530/h, ALAG was 0.242h. The correlation between preditictive concentrationand true concentration was 0.98; mean absolute weighted residual was 6±6%.3. There was better result when validation data set was added in the finalregression model. The final population parameters were: CL was 0.019KL/h, V2was 0.170KL, Q was 0.071KL/h, V3 was 0.324 KL, KAwas 2.676/h, ALAG was0.230h. Mean absolute weighted residual was 11±10%, there were:＜5% was34.0%, 5%～10% was 22.9%, 10%～20% was 27.2%, 20%～30% was 10.9%,30%～40% was 2.5%,＞40% was 2.5%.Conclusion:1. The pharmacokinetic parameters analyzed by PKBP-N1 could represent theindividual pharmacokinetic information. Abbreviation AUC could accuratelypredict the total AUC.2. The final regreesion model by NONMEM of 22 patients and 151 patientscould estimate individual and population pharmacokinetic parameters accordingto individual basic information. Bayesian feedback could be used inindividualizing. 3. There was no significant difference between the final pharmacokineticparameters analyzed by PKBP-N1 and by NONMEM.