Flexible limited sampling model for monitoring tacrolimus in stable patients having undergone liver transplantation with samples 4 to 6 hours after dosing is superior to trough concentration

Abstract

Trough (C0) monitoring is not optimal for therapeutic drug monitoring of tacrolimus. To better estimate systemic exposure of tacrolimus and achieve clinical benefit, an improved therapeutic drug monitoring strategy should be developed. The authors examined which single and combination of time points best estimated the empiric "gold standard" AUC0-12h and developed and validated a new, flexible, and accurate limited sampling model for monitoring tacrolimus in patients having undergone liver transplantation. Twenty-three stable patients with full AUC0-12h were divided into two groups based on area under the concentration-time curve/dose. With multiple regression analysis, limited sampling formulae were derived and population-pharmacokinetic-based limited sampling models were developed and validated. A regression analysis was performed between either area under the concentration-time curves calculated with formulae or models with the reference trapezoidal AUC0-12h. Both formulae and models based on single samples C4-C6 (r2 = 0.94 [MPE/MAPE 0/7]-0.90 [2/8] and 0.97 [0/7]-0.97 [1/5]) showed excellent performance. The calculated area under the concentration-time curve target range for tacrolimus was 90 to 130 h*microg/L. Multiple point sampling performed better, especially when using models (r2 > 0.94). C0 was a less precise predictor of AUC0-12h compared with both formulae and models (r2's 0.68 [5/17] and 0.87 [2/14]). In conclusion, trough concentration monitoring is not an accurate method for assessing systemic exposure to tacrolimus in stable patients having undergone liver transplantation. This new limited sampling model, based on single time points C4-C6, shows excellent performance in estimating the AUC0-12h.