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Background and Objective <p>Tacrolimus therapeutic drug monitoring after kidney transplantation is primarily guided by the pre-dose concentration (<i>C</i><sub>0</sub>), assuming it reflects overall drug exposure. At the same time, the tacrolimus concentration-to-dose ratio (<i>C</i><sub>0</sub>/dose) has emerged as a marker associated with clinical outcomes after transplantation, suggesting that differences in peak (maximum concentration [<i>C</i><sub>max</sub>]) and total tacrolimus exposure (area under the concentration–time curve from 0 to 24 h [AUC<sub>0–24h</sub>]) may not be fully captured by <i>C</i><sub>0</sub> alone.</p> Methods <p>In 534 kidney transplant recipients followed for up to 13 months post-transplantation, 635 tacrolimus pharmacokinetic profiles with corresponding <i>C</i><sub>0</sub> values were analyzed. The <i>C</i><sub>0</sub>/dose category was defined using the <i>C</i><sub>0</sub>/dose ratio and classified as fast (&lt;1.05 ng·mL⁻<sup>1</sup>·mg⁻<sup>1</sup>, <i>n</i> = 344), intermediate (1.05–1.53, <i>n</i> = 127), or slow (≥1.54, <i>n</i> = 164). Analyses were restricted to measurements with <i>C</i><sub>0</sub> between 5.0 and 6.0 ng/mL to compare <i>C</i><sub>max</sub> and AUC<sub>0–24h</sub> across <i>C</i><sub>0</sub>/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated <i>C</i><sub>0</sub>-adjusted <i>C</i><sub>max</sub> and AUC<sub>0–24h</sub> in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when <i>C</i><sub>max</sub> was predicted using population pharmacokinetic models.</p> Results <p>Despite comparable <i>C</i><sub>0</sub> levels, the fast <i>C</i><sub>0</sub>/dose category was associated with substantially higher tacrolimus doses and had higher peak concentration and total exposure. Under immediate-release tacrolimus, <i>C</i><sub>max</sub> and AUC<sub>0–24h</sub> were 30 and 18% higher, respectively, compared with the slow category. Under extended-release tacrolimus, differences were more pronounced, with 86% higher <i>C</i><sub>max</sub> (estimate: 1.86, 95% confidence interval 1.61–2.13) and 46% higher AUC<sub>0–24h</sub> (estimate: 1.45, 95% confidence interval 1.35–1.55). The intermediate category showed a smaller but consistent increase in exposure. Higher <i>C</i><sub>max</sub> and AUC<sub>0–24h</sub> relative to <i>C</i><sub>0</sub> in fast metabolizers remained consistent in the full cohort and when <i>C</i><sub>max</sub> was model predicted.</p> Conclusions <p>Tacrolimus <i>C</i><sub>0</sub> alone incompletely reflects the full pharmacokinetic profile and may miss clinically relevant peak-related toxicity. The <i>C</i><sub>0</sub>/dose ratio may help identify patients with disproportionate exposure, in whom more individualized therapeutic drug monitoring beyond <i>C</i><sub>0</sub> monitoring is recommended.</p>

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Low Tacrolimus C0/Dose Ratio is Associated with Higher Cmax and AUC Despite Similar Pre-dose Concentrations

  • 期刊论文

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  • 发表日期：

    2026年7月22日

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  • Amar D. Levens,
  • Teun van Gelder,
  • Armin Gelinck,
  • Soufian Meziyerh,
  • Aiko P. J. de Vries,
  • Danny van der Helm,
  • Jesse J. Swen,
  • Dirk Jan A. R. Moes

摘要

Background and Objective

Tacrolimus therapeutic drug monitoring after kidney transplantation is primarily guided by the pre-dose concentration (C0), assuming it reflects overall drug exposure. At the same time, the tacrolimus concentration-to-dose ratio (C0/dose) has emerged as a marker associated with clinical outcomes after transplantation, suggesting that differences in peak (maximum concentration [Cmax]) and total tacrolimus exposure (area under the concentration–time curve from 0 to 24 h [AUC0–24h]) may not be fully captured by C0 alone.

Methods

In 534 kidney transplant recipients followed for up to 13 months post-transplantation, 635 tacrolimus pharmacokinetic profiles with corresponding C0 values were analyzed. The C0/dose category was defined using the C0/dose ratio and classified as fast (<1.05 ng·mL⁻1·mg⁻1, n = 344), intermediate (1.05–1.53, n = 127), or slow (≥1.54, n = 164). Analyses were restricted to measurements with C0 between 5.0 and 6.0 ng/mL to compare Cmax and AUC0–24h across C0/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated C0-adjusted Cmax and AUC0–24h in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when Cmax was predicted using population pharmacokinetic models.

Results

Despite comparable C0 levels, the fast C0/dose category was associated with substantially higher tacrolimus doses and had higher peak concentration and total exposure. Under immediate-release tacrolimus, Cmax and AUC0–24h were 30 and 18% higher, respectively, compared with the slow category. Under extended-release tacrolimus, differences were more pronounced, with 86% higher Cmax (estimate: 1.86, 95% confidence interval 1.61–2.13) and 46% higher AUC0–24h (estimate: 1.45, 95% confidence interval 1.35–1.55). The intermediate category showed a smaller but consistent increase in exposure. Higher Cmax and AUC0–24h relative to C0 in fast metabolizers remained consistent in the full cohort and when Cmax was model predicted.

Conclusions

Tacrolimus C0 alone incompletely reflects the full pharmacokinetic profile and may miss clinically relevant peak-related toxicity. The C0/dose ratio may help identify patients with disproportionate exposure, in whom more individualized therapeutic drug monitoring beyond C0 monitoring is recommended.