Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.
OBJECTIVE
This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years.


METHODS
In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2-6, 7-11, and 12-17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated.


RESULTS
A total of 130 patients (2-6 years, n = 45; 7-11 years, n = 39; 12-17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 micromol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients.


CONCLUSIONS
Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.
Hahn
Gabriele
G
Institut und Poliklinik für Radiologische Diagnostik Bereich Kinderradiologie am Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany.
Sorge
Ina
I
Gruhn
Bernd
B
Glutig
Katja
K
Hirsch
Wolfgang
W
Bhargava
Ravi
R
Furtner
Julia
J
Born
Mark
M
Schröder
Cornelia
C
Ahlström
Håkan
H
Kaiser
Sylvie
S
Moritz
Jörg Detlev
JD
Kunze
Christian Wilhelm
CW
Shroff
Manohar
M
Stokland
Eira
E
Trnkova
Zuzana Jirakova
ZJ
Schultze-Mosgau
Marcus
M
Reif
Stefanie
S
Bacher-Stier
Claudia
C
Mentzel
Hans-Joachim
HJ
D002648:Child; D002675:Child, Preschool; D003287:Contrast Media / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000009:adverse effects / Q000379:methods*; D008297:Male; D009942:Organometallic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
D003287:Contrast Media; D009942:Organometallic Compounds; C090600:gadobutrol