Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf ® , a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf ® and Envarsus ® XR) and various generic versions of Prograf ® are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf ® , Advagraf ® and Envarsus ® XR are not bioequivalent [in terms of the area under the concentration–time curve from 0 to 24 h (AUC 0–24 ) or the minimum concentration ( C min )]. Patients may require a daily dosage increase if converted from Prograf ® to Advagraf ® , while a daily dosage reduction appears necessary for conversion from Prograf ® to Envarsus ® XR. Prograf ® itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC 0–24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further