Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation
© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
AIM: Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off-label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy.
METHODS: In total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens.
RESULTS: The alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range.
CONCLUSION: Alemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:89 |
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| Enthalten in: |
British journal of clinical pharmacology - 89(2023), 4 vom: 14. Apr., Seite 1471-1485 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zwart, Tom C [VerfasserIn] |
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| Links: |
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| Themen: |
3A189DH42V |
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| Anmerkungen: |
Date Completed 20.03.2023 Date Revised 29.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15608 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM34921980X |
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| 100 | 1 | |a Zwart, Tom C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 20.03.2023 | ||
| 500 | |a Date Revised 29.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a AIM: Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off-label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy | ||
| 520 | |a METHODS: In total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens | ||
| 520 | |a RESULTS: The alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range | ||
| 520 | |a CONCLUSION: Alemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a alemtuzumab | |
| 650 | 4 | |a kidney transplantation | |
| 650 | 4 | |a personalized dosing | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 4 | |a population pharmacokinetic modelling | |
| 650 | 7 | |a Alemtuzumab |2 NLM | |
| 650 | 7 | |a 3A189DH42V |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 700 | 1 | |a Bezstarosti, Suzanne |e verfasserin |4 aut | |
| 700 | 1 | |a Achini, Federica R |e verfasserin |4 aut | |
| 700 | 1 | |a Reinders, Marlies E J |e verfasserin |4 aut | |
| 700 | 1 | |a Schilham, Marco W |e verfasserin |4 aut | |
| 700 | 1 | |a Heidt, Sebastiaan |e verfasserin |4 aut | |
| 700 | 1 | |a Guchelaar, Henk-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a de Fijter, Johan W |e verfasserin |4 aut | |
| 700 | 1 | |a Moes, Dirk Jan A R |e verfasserin |4 aut | |
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