Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy
Background and Objectives Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on “active” rATG population PK (popPK) analysis, while “total” rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. Methods Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5–3 mg/kg) within 3 days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. Results A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47 years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), $ CD4^{+} $ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. Conclusions This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Clinical pharmacokinetics - 62(2023), 8 vom: 07. Juni, Seite 1081-1091 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Takahashi, Takuto [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s40262-023-01252-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
SPR052581233 |
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| 520 | |a Background and Objectives Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on “active” rATG population PK (popPK) analysis, while “total” rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. Methods Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5–3 mg/kg) within 3 days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. Results A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47 years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), $ CD4^{+} $ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. Conclusions This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest. | ||
| 700 | 1 | |a Teramoto, Masahiro |4 aut | |
| 700 | 1 | |a Matsumoto, Kana |4 aut | |
| 700 | 1 | |a Jaber, Mutaz M. |4 aut | |
| 700 | 1 | |a Tamaki, Hiroya |4 aut | |
| 700 | 1 | |a Ikegame, Kazuhiro |4 aut | |
| 700 | 1 | |a Yoshihara, Satoshi |4 aut | |
| 700 | 1 | |a Kaida, Katsuji |4 aut | |
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