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

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 [C_max]) and total tacrolimus exposure (area under the concentration-time curve from 0 to 24 h [AUC_0-24h]) may not be fully captured by C₀ alone.

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 C_max and AUC_0-24h across C₀/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated C₀-adjusted C_max and AUC_0-24h in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when C_max was predicted using population pharmacokinetic models.

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, C_max and AUC_0-24h were 30 and 18% higher, respectively, compared with the slow category. Under extended-release tacrolimus, differences were more pronounced, with 86% higher C_max (estimate: 1.86, 95% confidence interval 1.61-2.13) and 46% higher AUC_0-24h (estimate: 1.45, 95% confidence interval 1.35-1.55). The intermediate category showed a smaller but consistent increase in exposure. Higher C_max and AUC_0-24h relative to C₀ in fast metabolizers remained consistent in the full cohort and when C_max was model predicted.

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.