Population Pharmacokinetics of Melphalan in a Large Cohort of Autologous and Allogeneic Hematopoietic Cell Transplantation Recipients: Towards Individualized Dosing Regimens

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/m 2 , a twocompartment 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.

Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide–Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma

“…A literature search found 6 published population PK studies for melphalan after administration of melphalan. 15,16,18 Of these studies, 4 had only data after high doses in connection with stem cell transplant, and no study had data for repeated cycles of treatment. In 5 of the studies, a 2-compartment model was stated to best fit the data, and in 1 study a 1-compartment model was selected.…”

“…A literature search found 6 published population PK studies for melphalan after administration of melphalan 15,16,18 . Of these studies, 4 had only data after high doses in connection with stem cell transplant, and no study had data for repeated cycles of treatment.…”

Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation

“…In summary, this analysis adds to the growing literature supporting the importance of TDM and precision drug dosing of conditioning regimen agents and their association with allo-HCT outcomes in both unmodified and TCD-selected allo-HCTs. 1 13 , 24 , 34 , 35 Moreover, our group is actively studying precision conditioning regimen drug dosing in the context of TCD allo-HCT in an actively accruing, prospective clinical trial (NCT04872595).…”