Solans, BP;
Chiesa, R;
Doncheva, B;
Prunty, H;
Veys, P;
Trocóniz, IF;
Standing, JF;
(2020)
Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning.
British Journal of Clinical Pharmacology
, 86
(8)
pp. 1537-1549.
10.1111/bcp.14260.
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Abstract
AIM: Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric hematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post‐HSCT period. The main objectives were: (i) to establish a mechanistic PKPD model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan‐based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT. METHODS: data on 126 patients, 72 receiving busulfan (7 months‐18 years, 5.1–47.0 Kg) and 54 treosulfan (4 months–17 years, 3.8–35.8 Kg), were collected. 8,935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. ANC profiles were modelled semi‐mechanistically accounting for transplant effects and differing set points pre‐ and post‐transplant. RESULTS: Pharmacokinetics were best described by two‐compartment models for both drugs. The Friberg semi‐mechanistic neutropenia model was applied with a linear model for busulfan and an Emax model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the ANC begin to grow after HSCT. CONCLUSIONS: A semi‐mechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab co‐administration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion.
| Type: | Article |
|---|---|
| Title: | Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bcp.14260 |
| Publisher version: | https://doi.org/10.1111/bcp.14260 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | busulfan, conditioning, hematopoietic stem cell transplant, population modelling, treosulfan |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10092677 |
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