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Pharmaceutical Research

, 36:45 | Cite as

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

  • Tong Lu
  • Xu Zhu
  • Shansen Xu
  • Mingming Zhao
  • Xueshi Huang
  • Zhanyou Wang
  • Limei ZhaoEmail author
Research Paper
First Online:
  • 33 Downloads

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.

KEY WORDS

dosage optimization genetic polymorphisms nephrotic syndrome population pharmacokinetics tacrolimus 

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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Notes

Supplementary material

11095_2019_2579_Fig5_ESM.png (191 kb)
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)

11095_2019_2579_MOESM1_ESM.tif (425 kb)
High Resolution Image (TIF 425 kb)
11095_2019_2579_Fig6_ESM.png (348 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)

11095_2019_2579_MOESM2_ESM.tif (378 kb)
High Resolution Image (TIF 378 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tong Lu
    • 1
    • 2
  • Xu Zhu
    • 1
  • Shansen Xu
    • 1
  • Mingming Zhao
    • 1
  • Xueshi Huang
    • 3
  • Zhanyou Wang
    • 4
  • Limei Zhao
    • 1
    • 2
    Email author
  1. 1.Department of PharmacyShengjing Hospital of China Medical UniversityShenyangChina
  2. 2.School of Life Science and BiopharmaceuticsShenyang Pharmaceutical UniversityShenyangChina
  3. 3.College of Life and Health SciencesNortheastern UniversityShenyangChina
  4. 4.Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of educationChina Medical UniversityShenyangChina

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