Clinical pharmacokinetics · 2026
Low Tacrolimus C0/Dose Ratio is Associated with Higher Cmax and AUC Despite Similar Pre-dose Concentrations.
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Levens Amar D, van Gelder Teun, Gelinck Armin, Meziyerh Soufian, de Vries Aiko P J, van der Helm Danny, Swen Jesse J, Moes Dirk Jan A R
Аннотация
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.
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.