Population Pharmacokinetics of Phosphocreatine and its metabolite
Creatine in Children with Myocarditis
Abstract
Aims This study aimed to develop a parent-metabolite joint population
pharmacokinetic model to characterize the pharmacokinetic (PK) profile
for phosphocreatine (PCr) and its metabolite creatine (Cr) in children
with myocarditis, and to use this model to study the PK profile of
different dosing schemes. Methods One hundred pediatric patients with
myocarditis were enrolled. Blood samples were collected at baseline and,
approximately 30, 40 or 50, 75 and 180 min after a single dose of
phosphocreatine sodium. Plasma PCr and Cr concentrations were determined
using a HPLC-MS/MS method. A nonlinear mixed-effects model approach was
used to build the population pharmacokinetic model. After validation,
the model was used for simulations to evaluate the PK profile of
different dosing schemes. Results A total of 997 plasma concentrations
(498 for PCr and 499 for Cr) were included in the analysis. A
four-compartment chain model (central and peripheral compartments for
both PCr and Cr) with first-order elimination adequately characterized
the in vivo process of PCr and Cr. Allometric scaling based on
bodyweight was applied to the PK parameters. The covariate analysis
identified that the glomerular filtration rate (GFR) was strongly
associated with the Cr clearance. Bootstrap and visual predictive check
suggested a robust and reliable pharmacokinetic model was developed. The
simulation results showed that the PCr had no accumulation in vivo. With
the infusion of PCr, the concentration of Cr increased rapidly.
Conclusion The joint population pharmacokinetic model for PCr and Cr in
pediatric patients with myocarditis was successfully developed for the
first time.