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Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy

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Abstract

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.

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Acknowledgements

We thank all physicians, nurses, pharmacists, and other medical staff for their care of the patients in this study.

Author information

Author notes

  1. Takuto Takahashi and Masahiro Teramoto: equally contributed.

Authors and Affiliations

  1. Pediatric Stem Cell Transplantation, Boston Children’s Hospital/Dana Farber Cancer Institute, Boston, MA, USA

    Takuto Takahashi

  2. Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA

    Takuto Takahashi & Mutaz M. Jaber

  3. Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Hyogo, Japan

    Masahiro Teramoto, Hiroya Tamaki, Kazuhiro Ikegame, Satoshi Yoshihara & Katsuji Kaida

  4. Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe, Kyoto, Japan

    Kana Matsumoto

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  1. Takuto Takahashi
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Correspondence to Takuto Takahashi.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request after an approval from the study committee.

Author contributions

Conceptualization: TT, MT; methodology, computational analysis, writing—original draft preparation: TT; bioanalysis: KM; review of computational analysis: MJ; clinical sample acquisition: MT, HT, KI, SY, KK; data curation: MT; writing—review and editing: all authors.

Funding

Not applicable.

Conflict of interest

The authors have no competing interests associated with this study.

Ethics approval

The present study was approved by the institutional review board at the Hyogo Medical University

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Patients and/or their legal guardians provided written consent to participate in the present study.

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Patients and/or their legal guardians provided written consent for publication of the present study.

Code availability

The code generated during the current study is available from the corresponding author on reasonable request after approval from the study committee.

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Supplementary file1 (DOCX 22074 kb)

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Takahashi, T., Teramoto, M., Matsumoto, K. et al. Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy. Clin Pharmacokinet 62, 1081–1091 (2023). https://doi.org/10.1007/s40262-023-01252-4

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