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Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective

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Abstract

Aim

The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterize time-varying clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modeling of long-term follow-up data from our institution.

Methods

In total, 3674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were selected according to a previous study and well-accepted theoretical mechanisms. Model-informed individualized therapeutic regimens were also evaluated.

Results

A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h−1 (relative standard error: 5%). Allometrically scaled body size, hematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation.

Conclusions

By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimize CsA therapy. CsA dose adjustments should be considered in different postoperative periods.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported in part by grants from the ‘2019 Key Clinical Program of Clinical Pharmacy’ (No. shslczdzk06502), and ‘Weak Discipline Construction Project’ (No. 2016ZB0301-01) of Shanghai Municipal Health and Family Planning Commission. We would like to thank Editage (www.editage.cn) for English language editing.

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Author notes

  1. Xiaoyan Qiu and Weiwei Qin have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China

    Junjun Mao, Xiaoyan Qiu, Weiwei Qin, Luyang Xu & Mingkang Zhong

  2. Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China

    Ming Zhang

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  1. Junjun Mao
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Contributions

JJM, XYQ, and WWQ participated in the research design; JJM, XYQ, WWQ, LYX, MZ, and MKZ implemented and conducted the study; JJM, XYQ, and WWQ performed the research and analyzed the data. JJM and WWQ drafted the manuscript, which was revised and approved by all the authors. There are no other relationships or activities that could appear to have influenced the submitted work.

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Correspondence to Xiaoyan Qiu or Weiwei Qin.

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There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. All authors have no conflicts of interest to declare.

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All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Mao, J., Qiu, X., Qin, W. et al. Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective. Pharm Res 38, 1873–1887 (2021). https://doi.org/10.1007/s11095-021-03114-9

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