Population pharmacokinetic modelling of busulfan and the influence of body composition in paediatric Fanconi anaemia patients. Issue 5 (23rd January 2020)

• Record Type: Journal Article
• Authors: van Hoogdalem, Matthijs W.; Emoto, Chie; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Mehta, Parinda A.; Vinks, Alexander A.
• Is Part Of: British journal of clinical pharmacology. Volume 86:Issue 5(2020)
• Page Start: 933
• Page End: 943
• Publication Date: 2020-01-23
• Subjects: busulfan -- Fanconi anaemia -- paediatrics -- population pharmacokinetic modelling; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14202
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: Fanconi anaemia (FA) is a rare disorder characterized by progressive bone marrow failure that requires haematopoietic cell transplantation (HCT). Busulfan is used in conditioning regimens prior to HCT. Doses used in non‐FA patients cause life‐threatening toxicities in FA patients and data on busulfan pharmacokinetics (PK) in this population are limited. This study characterized busulfan PK in paediatric FA patients using population PK modelling and evaluated the effect of body composition on steady‐state concentrations ( C ss ). Methods: A total of 200 busulfan plasma concentrations in 29 FA patients from a recent study (Clinicaltrials.gov ; NCT01082133) were available for population PK modelling. The effect of different body size‐scaled doses and body compositions on C ss was investigated using population PK modelling. Results: Fat free mass (FFM) was identified as the best size descriptor in a two‐compartment busulfan PK model in FA patients. Conventional dosing, based on an amount of busulfan per kilogram of total body mass, resulted in higher C ss in FA patients with higher body mass index (BMI). A newly proposed FFM‐based dosing strategy would eliminate the observed trend of higher concentrations in high BMI patients, and achieve consistent C ss across a wide BMI spectrum. Conclusions: This is the first study to describe the population PK of busulfan in paediatric FA patients. The proposed model will facilitate PK model‐informed precision dosing. FFM‐based dosing is expected to improve the probability of achieving target C ss, particularly in obese patients, while minimizing the risk of overdosing.