Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-11-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.750433/full |
| _version_ | 1818740785899634688 |
|---|---|
| author | Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo |
| author_facet | Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo |
| author_sort | Amedeo De Nicolò |
| collection | DOAJ |
| description | Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations. |
| first_indexed | 2024-12-18T01:46:15Z |
| format | Article |
| id | doaj.art-60763e1cd80049c3a0135c3381f099e7 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-18T01:46:15Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-60763e1cd80049c3a0135c3381f099e72022-12-21T21:25:10ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-11-011210.3389/fphar.2021.750433750433Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric PatientsAmedeo De Nicolò0Michele Pinon1Alice Palermiti2Antonello Nonnato3Alessandra Manca4Jacopo Mula5Silvia Catalano6Francesco Tandoi7Renato Romagnoli8Antonio D’Avolio9Pier Luigi Calvo10Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, ItalyPediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, ItalyLaboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, ItalyClinical Biochemistry Unit, Department of Diagnostic Laboratory, A.O.U. Città della Salute e della Scienza Hospital, Turin, ItalyLaboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, ItalyLaboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, ItalyGeneral Surgery, Liver Transplant Center, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, ItalyGeneral Surgery, Liver Transplant Center, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, ItalyGeneral Surgery, Liver Transplant Center, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, ItalyLaboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, ItalyPediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, ItalyTacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.https://www.frontiersin.org/articles/10.3389/fphar.2021.750433/fullpharmacokineticsimmunosuppressantpharmacologypharmacokinetics-pharmacodynamicstransplantationpharmacokinectics |
| spellingShingle | Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients Frontiers in Pharmacology pharmacokinetics immunosuppressant pharmacology pharmacokinetics-pharmacodynamics transplantation pharmacokinectics |
| title | Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients |
| title_full | Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients |
| title_fullStr | Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients |
| title_full_unstemmed | Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients |
| title_short | Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients |
| title_sort | monitoring tacrolimus concentrations in whole blood and peripheral blood mononuclear cells inter and intra patient variability in a cohort of pediatric patients |
| topic | pharmacokinetics immunosuppressant pharmacology pharmacokinetics-pharmacodynamics transplantation pharmacokinectics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.750433/full |
| work_keys_str_mv | AT amedeodenicolo monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT michelepinon monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT alicepalermiti monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT antonellononnato monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT alessandramanca monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT jacopomula monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT silviacatalano monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT francescotandoi monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT renatoromagnoli monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT antoniodavolio monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients AT pierluigicalvo monitoringtacrolimusconcentrationsinwholebloodandperipheralbloodmononuclearcellsinterandintrapatientvariabilityinacohortofpediatricpatients |