Gunjan L Shah1,2, Jaap Jan Boelens3,4, Dean Carlow5, Andrew Lin6, Ryan Schofield5, Nancy Cruz Sitner1, Anna Alperovich1, Josel Ruiz1, Anthony Proli6, Parastoo Dahi1,2, Roni Tamari1,2, Sergio A Giralt1,2, Michael Scordo1,2, Rick Admiraal7,8. 1. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 3. Stem Cell Transplantation and Cellular Therapies Program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, NY, USA. 5. Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Pediatric Hematopoeitic Cell Transplantation Program, Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands. r.admiraal-4@prinsesmaximacentrum.nl. 8. Department of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands. r.admiraal-4@prinsesmaximacentrum.nl.
Abstract
BACKGROUND AND OBJECTIVES: High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. METHODS: Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. RESULTS: Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. CONCLUSIONS: The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.
BACKGROUND AND OBJECTIVES: High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. METHODS: Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. RESULTS: Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. CONCLUSIONS: The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.
Authors: S R Parmar; R Bookout; J F Shapiro; R Tombleson; J Perkins; J Kim; B Yue; M Tomblyn; M Alsina; T Nishihori Journal: Bone Marrow Transplant Date: 2014-03-24 Impact factor: 5.483
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Authors: Ryan C Schofield; Heather J Landau; Sergio A Giralt; Gunjan L Shah; Michael Scordo; Andrew Lin; Elaine Zanutto; Lakshmi V Ramanathan; Melissa S Pessin; Dean C Carlow Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2019-07-04 Impact factor: 3.205
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Authors: Parastoo B Dahi; Andrew Lin; Michael Scordo; Jessica R Flynn; Sean M Devlin; Josel D Ruiz; Lauren DeRespiris; Dean Carlow; Christina Cho; Oscar B Lahoud; Miguel-Angel Perales; Craig S Sauter; Jan Jaap Boelens; Rick Admiraal; Sergio A Giralt; Gunjan L Shah Journal: Transplant Cell Ther Date: 2022-05-08