The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients

Aims Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model‐predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady‐state tacrolimus area under the curve over a 12‐h dosing period (AUC ss,0–12h ). Methods All recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12‐h cross‐sectional observational pharmacokinetic–pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. Results Dose‐normalized tacrolimus AUC ss,0–12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose‐normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). Conclusions Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUC ss,0–12h and clearance. Skin changes and acne were associated with dose‐normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUC ss,0–12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.