A prospective pilot study of a novel alemtuzumab target concentration intervention strategy

Arnold, Danielle E.; Emoto, Chie; Fukuda, Tsuyoshi; Dong, Min; Vinks, Alexander A.; Lane, Adam; McIntosh, Kelly; Neumeier, Lisa; Lankester, Arjan C.; Achini, Federica; Teusink‐Cross, Ashley; Chandra, Sharat; Jordan, Michael B.; Nelson, Adam; Myers, Kasiani C.; Davies, Stella M.; Mehta, Parinda A.; Marsh, Rebecca

doi:10.1038/s41409-021-01460-1

Cited by 6 publications

(8 citation statements)

References 9 publications

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“…For ATLG, this still needs to be determined, but a correlation between exposure and outcome seems most likely. High alemtuzumab levels also seem to be correlated with delayed immune reconstitution, but data is still scarce, and more research is needed in order to define a therapeutic target and an optimal dosing regimen ( Marsh et al, 2016 ; Bhoopalan et al, 2020 ; Arnold et al, 2021 ; Dong et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The publication of Dong et al described the results of a patient cohort of 29 patients with non-malignant disease undergoing HSCT [median age 6.4 years (range 0.28–21.4)], who were enrolled in two different studies ( Marsh et al, 2017 ; Arnold et al, 2021 ). Alemtuzumab was given as a total dose of 1 mg/kg divided over days -14 to -10 in study 1 ( n = 17) and in study 2 as a total dose of 0.5–0.6 mg/kg.…”

Section: Serotherapymentioning

confidence: 99%

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Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

et al. 2022

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Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

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Section: Discussionmentioning

confidence: 99%

Section: Serotherapymentioning

confidence: 99%

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

et al. 2022

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“…Still, alemtuzumab is currently used for the indication of hyperinflammation, with subcutaneous low dosing implemented to overcome slow or absent T-cell recovery (Bhatt et al, 2020). TDM of alemtuzumab is mainly focused on preventing underdosing (Arnold et al, 2021). From a pharmacokinetic perspective, exposure of ATG is easier to control given the higher clearance compared to alemtuzumab.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept

et al. 2022

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Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient’s plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.

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“…Hence, a therapeutic range of 0.15‐0.6 mg/L has been proposed for HSCT recipients, 12 demonstrating increasingly clear relations of alemtuzumab exposure with lymphocyte recovery and clinical outcomes in this setting. These findings have supported a personalized approach, with body size 9–12 and baseline lymphocyte count 9,11 as potential markers to guide individualized alemtuzumab therapy in HSCT, and provided a rationale for exploring a model‐informed therapeutic drug monitoring (TDM)‐guided dosing strategy 18 . Similarly, an exposure‐response relationship has been suggested for alemtuzumab in CLL, 14 in which the probability of treatment response was dependent on alemtuzumab exposure.…”

Section: Introductionmentioning

confidence: 78%

“…These findings have supported a personalized approach, with body size [9][10][11][12] and baseline lymphocyte count 9,11 as potential markers to guide individualized alemtuzumab therapy in HSCT, and provided a rationale for exploring a model-informed therapeutic drug monitoring (TDM)guided dosing strategy. 18 Similarly, an exposure-response relationship has been suggested for alemtuzumab in CLL, 14 in which the probability of treatment response was dependent on alemtuzumab exposure.…”

Section: Introductionmentioning

confidence: 92%

Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation

Zwart

Bezstarosti

Achini

et al. 2022

Brit J Clinical Pharma

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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 twocompartmental model with first-order absorption and parallel first-order and timevarying 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.

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A prospective pilot study of a novel alemtuzumab target concentration intervention strategy

Cited by 6 publications

References 9 publications

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept

Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation

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