In:
Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 5 ( 2018-10), p. 558-566
Abstract:
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 6 cells (1 year). Postdose PBMC-TAC was 44, 30, and 27 pg/10 6 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.
Type of Medium:
Online Resource
ISSN:
0163-4356
DOI:
10.1097/FTD.0000000000000539
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
2048919-5
SSG:
15,3
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