Discussion
Although the pharmacokinetics of PCr has already been investigated in
adults, its pharmacokinetic characteristics in children is unclear and
its metabolite Cr was ignored. To the best of our knowledge, this is not
only the first PK study of PCr in children but also the first
comprehensive population pharmacokinetic model of PCr and its metabolite
Cr. In this study, the pharmacokinetic characteristics of PCr and Cr in
children were studied by population pharmacokinetic method and the
established joint model fitted the concentration data well. This study
could be helpful to further understand the PCr and Cr PK characteristics
in children and provide reference for pediatric clinical application.
In the base model development process, the structural model of both PCr
and Cr were tested with one-compartment model and two-compartment model
respectively. The PCr data was best fitted by a two-compartment model
which is in accordance with a previous report [10, 11]. The
structural model of Cr was best described by a two-compartment model
with an estimation of baseline level of Cr level (baseCr).
There is only PCr dose for each subject and Cr was generated by PCr
metabolism. The distribution volume of Cr and Fm of PCr
metabolized to Cr couldn’t be estimated at the same time. It has been
reported that large number of PCr were metabolized to Cr in animals
after intravenous administration of PCr, and the conversion rate was
about three-quarters [10]. In the concentration–time plots
(Supplemental Material 3 ), Cr concentration increased rapidly
after PCr infusion. In our study, we were more interested in knowing the
distribution of Cr in children. Therefore, the apparent distribution
volume of Cr was estimated and the fraction of PCr metabolized to Cr was
fixed so as to avoid identifiability problem in the model building.
There is no evidence that showed the exact ratio fraction of PCr to Cr
in humans. The Cr concentration increased rapidly with the infusion of
PCr seen in the concentration profiles and a general view is that a
large amount of PCr is metabolized to Cr to provide ATP after PCr
injection [5]. In this study, based on the results of animal
experiment from the reference [10], the Fm of PCr
converted to Cr was assumed to be 0.75. This setting could ensure the
estimation the PK parameters of Cr in children and it didn’t affect the
estimation of PCr parameters. To compare the estimation results of
different fraction assumptions, we developed a model based on the
fraction fixed 1 and the estimation results showed PCr parameters did
not change much.
BW was incorporated in the base model with an allometric exponent of
0.75 for the clearance parameters and 1 for the volume terms which
result in a large decrease in OFV. The addition of allometric scaling
made the base model more stable and accelerated the speed of modeling.
In this study, to find more factors that affect the in vivo behavior of
the PCr and Cr as much as possible, a large amount of information of
study sample were collected as covariates. After forward inclusion and
backward elimination, GFR was identified as key covariates to the
clearance of Cr. The influence of GFR on CLCr was
estimated with exponent of 0.311, which means high level of GFR level
lead to increase of Cr clearance. As GFR increased by 100%, Cr
clearance increased by 24%.
The final PCr and Cr model was evaluated by bootstrap and VPC method,
respectively. Results showed that the established model had good
stability and predictability. The parameters estimated by the final
model showed that distribution volume of the PCr central compartment
(VcPCr) was 8.22 L, distribution volume of the PCr
peripheral compartment (VpPCr) was 3.07 L, total
distribution volume was 11.29 L, and the clearance was 1.33 L/min in
children with 20 kg. The distribution volume of the Cr central
compartment (VcCr) was 2.39 L, distribution volume of
the Cr peripheral compartment (VpCr) was 2.9 L, and the
clearance was 0.0825 L/min in children with 20 kg. The
VpCr is larger than VcCr, suggesting
that Cr can be widely distributed in muscle and other tissues. This
study first reported the distribution characteristics of Cr in children
under the Fm set to 0.75. The typical value of Cr base
value (baseCr) is 66.6 μmol/L, which is about 8.73 mg/L, basically
consistent with the normal content in human body (7-13 mg/L) [20].
The evaluated model was applied to simulate different regimens for
subgroups with different age. The simulation results suggested that PCr
did not accumulate in vivo.
In conclusion, the joint population pharmacokinetic model for PCr and
its metabolite Cr in pediatric patients was successfully developed for
the first time. The model adequately described the pharmacokinetics of
both parent drug and metabolite with individual predicted value close to
the measured value. This model may be helpful for pediatric clinical
application of phosphocreatine.
Acknowledgements
The authors acknowledge the support of Haerbin laibotong pharmaceutical
co. LTD for the clinical trial from which the
Phosphocreatine
and Creatine pharmacokinetic data were derived.
Competing Interests
The authors declare no conflicts of interest.
Contributors
All authors contributed to the design and implementation of the study.
L.B.Z., Y.Y. and X.L.W. designed the study. N.S. and H.H. acquired the
data. M.Z., Y.Z. and H.H. analyzed the data and develop the
pharmacokinetic model. H.H. wrote the manuscript and L.B.Z., Y.Y. and
X.L.W. revised it.