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Multicenter-Based Population Pharmacokinetic Analysis of Ciclosporin in Hematopoietic Stem Cell Transplantation Patients

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Abstract

Purpose

To explore the contribution of physiological characteristics to variability in ciclosporin pharmacokinetics in hematopoietic stem cell transplantation patients.

Methods

Clinical data from 563 patients were collected from centers in three regions. Ciclosporin concentrations were measured using immunoassays. The patients’ demographics, hematological and biological indicators, coadministered drugs, region, and disease diagnosis were recorded from medical records. Data analysis was performed using NONMEM based on a one-compartment model to describe the pharmacokinetics of ciclosporin. The reliability and stability of the final model were evaluated using bootstrap resampling, goodness-of-fit plots, and prediction-corrected visual predictive checks.

Results

The population estimate of the clearance (CL) was 30.4 L/h, the volume of distribution (V) was 874.0 L and the bioavailability (F) was 81.1%. The between-subject variability in these parameters was 26.3, 68.0, and 110.8%, respectively. Coadministration of fluconazole, itraconazole, or voriconazole decreased CL by 17.6%, 28.4%, and 29.2%, respectively. Females’ CL increased by approximately 12.0%. In addition, CL and V decreased with hematocrit, total protein, and uric acid increase, and CL also decreased with age and aspartate aminotransferase increase. However, CL increased with creatinine clearance increase.

Conclusions

A multicenter-based population pharmacokinetic model of ciclosporin was established. The pharmacokinetics of ciclosporin exhibited discrepancies among different regions.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request

Abbreviations

CL:

Clearance

CMIA:

Chemiluminescent microparticle immunoassay

CsA:

Ciclosporin

ECLIA:

Electrochemiluminescence immunoassay

EMIT:

Enzyme amplification immunoassay

FFM:

Fat free mass

FOCE:

First-order conditional estimation method

FPIA:

Fluorescence polarization immunoassay

HSCT:

Hematopoietic stem cell transplantation

NFM:

Normal fat mass

NONMEM:

Nonlinear mixed effect model

OFV:

Objective function value

pc_VPC:

Prediction-corrected visual predictive check

Pop-PK:

Population pharmacokinetics

PROP:

Proportional residual error

RSE:

Relative standard error

RUV:

Residual unidentified variability

TCI:

Target concentration intervention

TDM:

Therapeutic drug monitoring

V:

Volume of distribution

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Author information

Author notes

  1. Ling Xue, Wen-juan Zhang and Ji-xin Tian contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China

    Ling Xue, Wen-wen Zhang, Xiao-liang Ding, Jing-jing Zhang & Li-yan Miao

  2. Department of Pharmacy, the Second Affiliated Hospital of Air Force Medical University, Xi’an, China

    Wen-juan Zhang & Lin-na Liu

  3. Department of Pharmacy, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Ji-xin Tian & Hai-hong Yan

Authors
  1. Ling Xue
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  2. Wen-juan Zhang
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Correspondence to Li-yan Miao.

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Xue, L., Zhang, Wj., Tian, Jx. et al. Multicenter-Based Population Pharmacokinetic Analysis of Ciclosporin in Hematopoietic Stem Cell Transplantation Patients. Pharm Res 37, 15 (2020). https://doi.org/10.1007/s11095-019-2740-2

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  • DOI: https://doi.org/10.1007/s11095-019-2740-2

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