Population pharmacokinetic modelling of busulfan and the influence of body composition in paediatric Fanconi anaemia patients

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 (Css ).

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 Css 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 Css 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 Css 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 Css , particularly in obese patients, while minimizing the risk of overdosing.

Keywords: Fanconi anaemia; busulfan; paediatrics; population pharmacokinetic modelling.

Conflict of interest statement

There are no competing interests to declare.

© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

BMI distribution for male (A) and female (B) patients in the study population (black circles). Black lines are locally weighted scatterplot smoothing curves through international cut‐off points for BMI for overweight (lower curve) and obesity (upper curve) proposed by Cole et al.32 The yellow area indicates overweight, whereas patients in the red area are considered obese. One patient (male, 22.4 years of age, BMI = 23.9 kg m−2) is not included in this graph, since overweight and obesity in adulthood is determined differently, ie, BMI greater than 25 and 30 kg m−2, respectively

Figure 2

Age versus height (A, B), weight (C, D) and BMI (E, F) for male (left column) and female (right column) patients (black circles) plotted with the NHANES data (yellow and purple shading for men and women, respectively), executed by Centers for Disease Control and Prevention (CDC) over the years 2005‐2014. The dashed line is a locally weighted scatterplot smoothing curve through the NHANES data

Figure 3

Goodness‐of‐fit plots for the final PK model. Population‐predicted (A) and individual‐predicted (B) busulfan concentrations vs observed concentrations (solid line, line of identity; dashed line, linear regression; open circles, observed data). Conditional weighted residuals (CWRES) vs (C) population‐predicted busulfan concentration and (D) time after start of the infusion (solid line, line of identity; dashed line, second‐order polynomial; open circles, observed data)

Figure 4

Prediction‐corrected visual predictive check (pcVCP) for the final model of busulfan. Open circles represent observed concentration. The solid red line represents the median of the observed concentration, and the shaded red area represents a simulation‐based 95% CI for the median. The solid blue lines represent the 95th and 5th percentiles of the observed data, and the simulation‐based 95% CIs for the 95th and 5th percentiles are shown as the shaded blue areas

Figure 5

Plasma concentration‐time profiles of intravenous busulfan for underweight (A, B), normal weight (C, D), and obese (E, F) patients following the first dose. The left column represents male patients, female patients are represented by the right column. The dashed line is the population‐based prediction, black circles are observed data, and the solid line is the individually predicted fit

Figure 6

Individual steady‐state concentrations (Css) following the initial dose (A, 0.6 and 0.8 mg kg−1 TBM) and simulated doses (B, 0.6 mg kg−1 TBM; C, 0.6 mg kg−1 FFM; D, 0.8 mg kg−1 FFM) plotted against the body mass index (BMI) of the patient. Open circles represent non‐obese patients and obese patients are represented by black circles. The dotted line represents the proposed upper Css limit (target ≤ 0.35 mg L−1). The solid line represents the linear regression line

Figure 7

Individual steady‐state concentration (Css) following simulated FFM‐ and TBM‐based doses. Open circles represent non‐obese patients and obese patients are represented by black squares. Solid horizontal lines represent median with interquartile range (IQR) per dosing regimen. Solid vertical lines mark 0.6, 0.8, 1.0 and 1.2 mg kg−1 dosing scenarios. The dotted line represents the proposed upper Css limit (target ≤ 0.35 mg L−1)

Figure 8

Estimated clearance (A) and volume of distribution (B) related population pharmacokinetic parameters in FA patients compared to reported values in non‐FA paediatric patients.13, 14, 15, 16, 17 All values, which were often expressed corresponding to the median weight of the population, were allometrically scaled to a total body weight of 70 kg, using the theoretical power exponents of 0.75 and 1.0 for clearance and volume, respectively. Both one‐ and two‐compartment models have been reported. Since one‐compartment models inherently include only one volume of distribution (Vd), this value was compared to the sum of the estimated volumes for the central and peripheral compartment (Vss) in two‐compartment models. Black circles represent the estimated value, with whiskers showing the 95% confidence interval of the mean estimate, unless stated otherwise. †Whiskers show the 90% confidence interval