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Model-informed precision dosing for alemtuzumab in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation
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  • Min Dong,
  • Chie Emoto,
  • Tsuyoshi Fukuda,
  • Danielle Arnold,
  • Parinda Mehta,
  • Rebecca Marsh,
  • Alexander Vinks
Min Dong
Cincinnati Children's Hospital Medical Center
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Chie Emoto
Cincinnati Children's Hospital Medical Center
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Tsuyoshi Fukuda
University of Cincinnati
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Danielle Arnold
Cincinnati Children's Hospital Medical Center
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Parinda Mehta
Cincinnati Children's Hospital Medical Center
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Rebecca Marsh
Cincinnati Children's Hospital Medical Center
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Alexander Vinks
Cincinnati Children's Hospital Medical Center
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Abstract

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

Peer review status:ACCEPTED

29 Jan 2021Submitted to British Journal of Clinical Pharmacology
02 Feb 2021Submission Checks Completed
02 Feb 2021Assigned to Editor
06 Feb 2021Reviewer(s) Assigned
10 Mar 2021Review(s) Completed, Editorial Evaluation Pending
13 Mar 2021Editorial Decision: Revise Major
24 Apr 20211st Revision Received
26 Apr 2021Submission Checks Completed
26 Apr 2021Assigned to Editor
26 Apr 2021Review(s) Completed, Editorial Evaluation Pending
27 Apr 2021Reviewer(s) Assigned
26 May 2021Editorial Decision: Accept