1. Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.
- Author
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Gustavsen MT, Midtvedt K, Robertsen I, Woillard JB, Debord J, Klaasen RA, Vethe NT, Bergan S, and Åsberg A
- Subjects
- Adult, Aged, Area Under Curve, Circadian Rhythm physiology, Drug Administration Schedule, Fasting physiology, Female, Graft Rejection blood, Graft Rejection immunology, Humans, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents adverse effects, Male, Middle Aged, Models, Biological, Prospective Studies, Tacrolimus administration & dosage, Tacrolimus adverse effects, Young Adult, Drug Monitoring methods, Graft Rejection prevention & control, Immunosuppressive Agents pharmacokinetics, Kidney Transplantation adverse effects, Tacrolimus pharmacokinetics
- Abstract
Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
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