Pharmacodynamic monitoring of ciclosporin and tacrolimus: insights from nuclear factor of activated t-cell-regulated gene expression in healthy volunteers
Background: - Although therapeutic drug monitoring of calcineurin inhibitor (CNI) concentrations is performed routinely in clinical practice, an identical concentration may lead to different effects in different patients. Although the quantification of nuclear factor of activated T-cell-reg...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
Feb 1, 2023
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| In: |
Therapeutic drug monitoring
Year: 2023, Volume: 45, Issue: 1, Pages: 87-94 |
| ISSN: | 1536-3694 |
| DOI: | 10.1097/FTD.0000000000001046 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1097/FTD.0000000000001046 Verlag, lizenzpflichtig, Volltext: https://journals.lww.com/drug-monitoring/Abstract/2023/02000/Pharmacodynamic_Monitoring_of_Ciclosporin_and.14.aspx 
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| Author Notes: | Yoana Aurelia Djaelani, MD, Thomas Giese, MD, Claudia Sommerer, MD, David Czock, MD |
| Summary: | Background: - Although therapeutic drug monitoring of calcineurin inhibitor (CNI) concentrations is performed routinely in clinical practice, an identical concentration may lead to different effects in different patients. Although the quantification of nuclear factor of activated T-cell-regulated gene expression (NFAT-RGE) is a promising method for measuring individual CNI effects, CNI pharmacodynamics are as of yet incompletely understood. - Methods: - CNI concentrations and NFAT-RGEs were quantified in 24 healthy volunteers receiving either ciclosporin or tacrolimus in 2 clinical trials. NFAT-RGE was measured using quantitative reverse transcription polymerase chain reaction tests of whole-blood samples. Pharmacokinetics and pharmacodynamics were analyzed using compartmental modeling and simulation. In addition, NFAT-RGE data from renal transplant patients were analyzed. - Results: - The average NFAT-RGE during a dose interval was reduced to approximately 50% with ciclosporin, considering circadian changes. The different effect-time course with ciclosporin and tacrolimus could be explained by differences in potency (IC50 204 ± 41 versus 15.1 ± 3.2 mcg/L, P < 0.001) and pharmacokinetics. Residual NFAT-RGE at the time of maximum concentration (RGEtmax) of 15% when using ciclosporin and of 30% when using tacrolimus was associated with similar average NFAT-RGEs during a dose interval. Renal transplant patients had similar but slightly stronger effects compared with healthy volunteers. - Conclusions: - Ciclosporin and tacrolimus led to similar average suppression of NFAT-RGE in a dose interval, despite considerably different RGEtmax. Pharmacodynamic monitoring of average NFAT-RGE should be considered. When using NFAT-RGE at specific time points, the different effect-time courses and circadian changes of NFAT-RGEs should be considered. |
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| Item Description: | Gesehen am 03.03.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1536-3694 |
| DOI: | 10.1097/FTD.0000000000001046 |