Discussion
In the present study, AUC prediction based on C6 was the
most accurate one-point blood sampling strategy. Watanabe et
al .9 reported that the AUC of busulfan was best
predicted by C6 in pediatric hematopoietic stem cell
transplant recipients, supporting the results of the present study. The
reason for the poor predictive performance of AUC based on
C1 could be because the individual differences in the
absorption phase were smaller than in the elimination phase due to the
intravenous administration of busulfan. C2 represents
the blood sampling immediately after the end of busulfan infusion and
may reflect the sampling of the distribution phase. Therefore, the blood
concentrations may significantly change within a few minutes, which
might explain the weaker relationship between the predicted AUC based on
C2 and the actual AUC.
In the present study, the predictive performance of AUC based on
C6 was lower (r2 = 0.789) than
that reported by Watanabe et al. 9(r2 = 0.929). More than 60% of all patients
weighed ≥23 kg in that study, whereas in our study, 24% of the patients
weighed ≥23 kg, which might have reduced the accuracy of predicted AUC
based on C6. In fact, from the predictive performance of
AUC performance by body weight, the predicted AUC based on
C6 was highly precise in adolescents.
In infants and young children, the accuracy of AUC predicted by
one-point sampling with C6 was poor. Kishimoto et
al .10 reported that errors in AUC prediction based on
C6 were higher in young children and infants using the
Monte Carlo simulation in the population pharmacokinetic model.
Furthermore, McCune et al .6 reported that the
accuracy of prediction for busulfan to reach the therapeutic range was
lower in patients younger than five years than in adolescent patients
using the population pharmacokinetic model. Therefore, in early
childhood, the busulfan pharmacokinetics significantly varies among
individuals, and predicting AUC by the one-point sampling strategy may
not be sufficient. In the present study, the AUC prediction based on
C3 and C6 using the two-point sampling
strategy was acceptable even for infants and young children. In the
validation cohort, more than half of the patients had more than 15%
errors with the one-point sampling strategy compared to the actual AUC.
Errors >15% are a deviation from the guidelines on
bioanalytical method validation in pharmaceutical
development,11 which states that the accuracy and
precision should be within ±15% deviation of the theoretical
concentration. Thus, in infants and young children, the AUC should be
predicted using the two-point sampling strategy.
In the one-point sampling strategy, the LSS equation for AUC was 2.866
C6 + 108.9 in adolescent patients. Consequently, the
target C6 was 360–500 ng/mL for myeloablative
conditioning (target AUC, 75–100 mg/L × h) and 200–300 ng/mL for
reduced-intensity conditioning (target AUC, 45–65 mg/L × h). In
contrast, in the two-point sampling strategy, the target
C3 depended on C6 and target AUC. It
should be noted that the accuracy of the predicted AUC by LSS will
decrease if the blood sampling time is significantly different from the
correct sampling time. Thus, it is important to pay close attention to
blood sampling times.
Concomitant medications that may affect the busulfan pharmacokinetics
should be considered in the interpretation of our findings. Kangarlooet al .12 reported that phenytoin, an
anticonvulsant agent, increased the busulfan clearance. In the present
study, levetiracetam or clonazepam were used as anticonvulsants, which
do not affect the busulfan pharmacokinetics.13,14Therefore, the anticonvulsant agent did not have a significant effect on
the busulfan pharmacokinetics in the present study.
The present study also has certain limitations. It remains unclear why
busulfan pharmacokinetics varies significantly in infants and young
children. Polymorphisms in glutathione S -transferase
(GST )15 affect busulfan pharmacokinetics.
Additionally, age-dependent variations in intrinsic busulfan clearance
were reported to be associated with higher GST
activity16; thus, differences in the GST expression
might explain individual differences in busulfan pharmacokinetics.
Further investigation is warranted to establish the parameters for
personalized administration of busulfan.
In conclusion, the AUC of busulfan could be predicted based on
C6 in adolescent patients. However, for infants and
young children, there was substantial inter-individual variation in
busulfan pharmacokinetics and the two-point sampling strategy was
necessary for accurate AUC prediction.