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Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

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Abstract

Purpose

The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients.

Methods

Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus.

Results

The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers.

Conclusions

A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.

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Abbreviations

95% CIs :

95% confidence intervals

ALB :

Albumin

ALT :

Alanine aminotransferase

AST :

Aspartate aminotransferase

C0 :

Whole blood trough concentrations

CL:

Clearance

CWRES :

Conditional weighted residuals

CYP3A4:

Cytochrome P450 3A4

CYP3A5 :

Cytochrome P450 3A5

DV :

Observed concentration

F:

Bioavailability

HCT :

Hematocrit

HGB :

Hemoglobin

IPRED:

Individual predicted concentration

MDR1 :

Multiple drug resistance 1

MRP2 :

Multidrug resistance -associated protein 2

NPDE :

Normalized prediction distribution errors

OFV :

Objective function value

PRED :

Predicted concentration

PsN :

Perl-Speaks-NONMEM

PXR :

Pregnane X receptor

RBC :

Red blood cells

SNPs:

Single nucleotide polymorphisms

SUMO4 :

Small ubiquitin-related modifier 4

Vd:

Volume of distribution

VPC :

Visual predictive check

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Author notes

  1. Tong Lu and Xu Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Tong Lu, Xu Zhu, Shansen Xu, Mingming Zhao & Limei Zhao

  2. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Tong Lu & Limei Zhao

  3. College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China

    Xueshi Huang

  4. Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of education, China Medical University, Shenyang, 110122, China

    Zhanyou Wang

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  1. Tong Lu
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Correspondence to Limei Zhao.

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Figure S1

Correlations between covariates. WT weight, ALB albumin, ALT alanine aminotransferase, AST aspartate aminotransferase, RBC red blood cells, HGB hemoglobin, HCT hematocrit. (PNG 190 kb)

High Resolution Image (TIF 425 kb)

Figure S2

Effects of covariates on tacrolimus oral clearance (L/h). AST aspartate aminotransferase, ALT alanine aminotransferase, ALB albumin, HGB hemoglobin, HCT hematocrit, RBC red blood cells, CYP3A4 Cytochrome P450 3A4, CYP3A5 Cytochrome P450 3A5, MDR1 Multiple drug resistance 1, MRP2 Multidrug resistance -associated protein 2, SUMO4 Small ubiquitin-related modifier 4, NR1I2 (PXR) Pregnane X receptor. (PNG 348 kb)

High Resolution Image (TIF 378 kb)

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Lu, T., Zhu, X., Xu, S. et al. Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome. Pharm Res 36, 45 (2019). https://doi.org/10.1007/s11095-019-2579-6

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