Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations

Sebastian P A Rosser; Samiuela Lee; Shruti Kohli; Steven J Keogh; Jason Chung; Tracey O'Brien; Christopher Fraser; Andrew J McLachlan; Peter J Shaw; Christa E Nath

doi:10.1111/bcp.15599

Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations

Br J Clin Pharmacol. 2023 Apr;89(4):1413-1424. doi: 10.1111/bcp.15599. Epub 2022 Nov 28.

Authors

Sebastian P A Rosser^{1

2

3}, Samiuela Lee^{2

4}, Shruti Kohli³, Steven J Keogh³, Jason Chung^{1

2}, Tracey O'Brien^{5

6}, Christopher Fraser⁷, Andrew J McLachlan⁸, Peter J Shaw^{1

3}, Christa E Nath^{2

3

8}

Affiliations

¹ The Children's Hospital at Westmead Clinical School, University of Sydney, Sydney, Australia.
² Department of Biochemistry, The Children's Hospital at Westmead, Sydney, Australia.
³ Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, Australia.
⁴ School of Chemical and Biomedical Engineering, University of Sydney, Sydney, Australia.
⁵ Kids Cancer Centre, Sydney Children's Hospital at Randwick, Randwick, Australia.
⁶ School of Women and Children's Health, Faculty of Medicine, University of New South Wales, Randwick, Australia.
⁷ Queensland Children's Hospital, South Brisbane, Australia.
⁸ Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

PMID: 36369677
DOI: 10.1111/bcp.15599

Abstract

Aim: To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration-time curve, AUC_0→∞ ) through dosing simulations.

Methods: A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2-17.0 years) receiving three daily age-guided doses (10-14 g/m² ). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood-ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC_0→∞ values were evaluated using age, body surface area (BSA) and model-based dosing regimens, targeting 4800 mg*h/L.

Results: Treosulfan concentration data were described using a one-compartment PK model with first-order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9-18.1) L/h and 41.9 (38.8-45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model-based dosing regimen more accurately achieved the target AUC_0→∞ (58.3%) over the age (42.6%) and BSA-based (51.3%) regimens.

Conclusion: Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model-informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC_0→∞ were not influenced by patient disease.

Keywords: NONMEM; chemotherapy; modelling and simulation; oncology; population analysis; treosulfan.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Body Weight
Busulfan* / pharmacokinetics
Child
Child, Preschool
Hematopoietic Stem Cell Transplantation* / adverse effects
Humans
Infant
Prospective Studies

Substances

treosulfan
Busulfan