INTRODUCTION: Tacrolimus (TAC) is an immunosuppressive drug used after organ transplantation. Dosing is adjusted using whole blood (WB-TAC) measurements. Patients within the therapeutic WB-TAC window still experience rejections and adverse effects. Alternative monitoring methods are therefore warranted. The authors developed a method for measuring TAC in peripheral blood mononuclear cell (PBMC) isolates (PBMC-TAC) and performed a pharmacokinetic study in a cohort of kidney transplant patients during the first year after transplantation. METHODS: PBMCs were isolated from whole blood by gradient centrifugation. After methanol-based extraction, liquid chromatography with tandem mass spectrometry was used to determine TAC in the extract. PBMC-TAC was normalized to the number of cells and alternatively to the protein amount in cells. Predose and postdose (1.5 hours) samples from kidney transplant patients were collected at 1 week, 6 weeks, and 1 year after transplantation. WB-TAC was measured using immunoassay. RESULTS: The PBMC-TAC assay fulfilled the validation criteria of the European Medicines Agency guidelines. Twenty-nine patients completed the study. Predose PBMC-TAC was (median) 23 (1 week), 33 (6 weeks), and 27 pg/10 cells (1 year). Postdose PBMC-TAC was 44, 30, and 27 pg/10 cells at 1 week, 6 weeks, and 1 year after transplantation, respectively. Predose WB-TAC (median) was 5.0, 6.0, and 5.4 mcg/L, and postdose WB-TAC was 10.5, 8.3, and 9.1 mcg/L, respectively, at 1 week, 6 weeks, and 1 year after transplantation. Whole blood and PBMC-TAC correlated at all timepoints (rho 0.40-0.82, P < 0.05) except before dosage at 6 weeks. PBMC-TAC normalized to the number of cells, and the amount of protein was modestly correlated (rho 0.36-0.81, P < 0.056). CONCLUSIONS: The correlation between WB-TAC and PBMC-TAC is modest during the first-year posttransplantation. Normalization of PBMC-TAC to cells or protein may yield different results. PBMC-TAC is increased 1.5 hours after dose at 1 week after transplantation, but not after 6 weeks or 1 year, indicating altered distribution kinetics.
INTRODUCTION:Tacrolimus (TAC) is an immunosuppressive drug used after organ transplantation. Dosing is adjusted using whole blood (WB-TAC) measurements. Patients within the therapeutic WB-TAC window still experience rejections and adverse effects. Alternative monitoring methods are therefore warranted. The authors developed a method for measuring TAC in peripheral blood mononuclear cell (PBMC) isolates (PBMC-TAC) and performed a pharmacokinetic study in a cohort of kidney transplant patients during the first year after transplantation. METHODS: PBMCs were isolated from whole blood by gradient centrifugation. After methanol-based extraction, liquid chromatography with tandem mass spectrometry was used to determine TAC in the extract. PBMC-TAC was normalized to the number of cells and alternatively to the protein amount in cells. Predose and postdose (1.5 hours) samples from kidney transplant patients were collected at 1 week, 6 weeks, and 1 year after transplantation. WB-TAC was measured using immunoassay. RESULTS: The PBMC-TAC assay fulfilled the validation criteria of the European Medicines Agency guidelines. Twenty-nine patients completed the study. Predose PBMC-TAC was (median) 23 (1 week), 33 (6 weeks), and 27 pg/10 cells (1 year). Postdose PBMC-TAC was 44, 30, and 27 pg/10 cells at 1 week, 6 weeks, and 1 year after transplantation, respectively. Predose WB-TAC (median) was 5.0, 6.0, and 5.4 mcg/L, and postdose WB-TAC was 10.5, 8.3, and 9.1 mcg/L, respectively, at 1 week, 6 weeks, and 1 year after transplantation. Whole blood and PBMC-TAC correlated at all timepoints (rho 0.40-0.82, P < 0.05) except before dosage at 6 weeks. PBMC-TAC normalized to the number of cells, and the amount of protein was modestly correlated (rho 0.36-0.81, P < 0.056). CONCLUSIONS: The correlation between WB-TAC and PBMC-TAC is modest during the first-year posttransplantation. Normalization of PBMC-TAC to cells or protein may yield different results. PBMC-TAC is increased 1.5 hours after dose at 1 week after transplantation, but not after 6 weeks or 1 year, indicating altered distribution kinetics.
Authors: Pere Fontova; Helena Colom; Raül Rigo-Bonnin; Lisanne N van Merendonk; Anna Vidal-Alabró; Nuria Montero; Edoardo Melilli; Maria Meneghini; Anna Manonelles; Josep M Cruzado; Juan Torras; Josep Maria Grinyó; Oriol Bestard; Nuria Lloberas Journal: Front Pharmacol Date: 2021-03-17 Impact factor: 5.810
Authors: Ingvild Andrea Kindem; Anna Bjerre; Anders Åsberg; Karsten Midtvedt; Stein Bergan; Nils Tore Vethe Journal: Ther Drug Monit Date: 2021-06-01 Impact factor: 3.681
Authors: Linda G Franken; Marith I Francke; Louise M Andrews; Ron H N van Schaik; Yi Li; Lucia E A de Wit; Carla C Baan; Dennis A Hesselink; Brenda C M de Winter Journal: Eur J Drug Metab Pharmacokinet Date: 2022-04-20 Impact factor: 2.569
Authors: Aliede E In 't Veld; Hendrika W Grievink; Mahdi Saghari; Frederik E Stuurman; Marieke L de Kam; Aiko P J de Vries; Brenda C M de Winter; Jacobus Burggraaf; Adam F Cohen; Matthijs Moerland Journal: Int J Mol Sci Date: 2019-09-23 Impact factor: 5.923
Authors: Marith I Francke; Dennis A Hesselink; Yi Li; Birgit C P Koch; Lucia E A de Wit; Ron H N van Schaik; Lin Yang; Carla C Baan; Teun van Gelder; Brenda C M de Winter Journal: Br J Clin Pharmacol Date: 2020-11-24 Impact factor: 4.335