Gadobutrol has a good safety profile for children

A prospective international study on the macrocyclic contrast agent gadobutrol in patients younger than two years showed a biodistribution similar to that of older patients. Safety and qualitative efficacy of gadobutrol was confirmed.

Available data show a good safety profile of gadobutrol (Gadavist^®, Bayer Healthcare) in MR imaging. However, patients younger than two years deserve distinct attention. Absorption, distribution and elimination of contrast agent might differ from older patients. They may also be more susceptible to adverse drug events.
Christian Kunze and colleagues, Germany, USA and Canada, performed a prospective pharmacokinetic and safety study on the use of gadobutrol in children younger than two years, including term newborns.

Method

The open label, international study took place at nine institutions in Germany, the USA and Canada.
44 patients younger than two years participated in the study. Nine of them were younger than two months. All of them had normal kidney function, expressed by the estimated globular filtration rate, eGFR.

1.0 mol/L gadobutrol was administered intravenously at the standard dose of 0.1 mL/kg body weight and a flow rate of 0.5 to 1.0 mL/s.
The babies and toddlers were sedated or anesthetized before examined with a 1.5 T MRI device. Different body parts were subject of the examination.

Blood samples for pharmacokinetics were taken at three different time points after injection (15-60 min., 2-4 h, 6-8 h). The following pharmacokinetic data were reported:

• The area under the plasma concentration curve AUC0-t from administration to eight hours [μmol·h/L]
• Total clearance from plasma, CL [L/h per kg body weight]
• Volume of distribution at steady state, Vss, [L/kg]
• Elimination half-life, t1/2 [h]
• Plasma concentrations at 20 and 30 min. after injection derived from a simulation based on a validated pharmacokinetic model [µmol/L]

Board-certified pediatric radiologists assessed the image quality and their diagnostic confidence on a four- or five-point scale. All adverse events were reported for safety evaluation. The young patients were followed up to eight days after MRI examination.

Results

Pharmacokinetics (PK): 43 patients were eligible for PK analysis.
The AUC showed a homogenous decline of gadobutrol in plasma over eight hours. Patients younger than two months had a slightly higher though no statistically significant AUC. The concentration of contrast agent was below 10 µmol/L after eight hours in all patients.

Total clearance from plasma depended on age and body weight, with a median of 0.128 L/h per kg body weight.
The median value of volume of distribution at steady state was 0.277 L/kg. The median elimination half-life was 1.68 h. Simulated plasma concentrations at 20 and 30 min. after injection were 339 µmol/L (C20) und 292 µmol/L (C30).

Image Quality: The readers valued 91% (40/44) of all unenhanced and 93.2% (41/44) of the images as “excellent” for basic technical quality. Overall contrast quality was rated as “good” or “excellent” in 93.2% of all cases.
In contrast-enhanced MRI, the diagnostic confidence was evaluated as “very confident” in 97.7% of all cases. Only 54.6% of the unenhanced images reached the same confidence level.

Safety: Mild adverse events occurred in 18 of the 44 patients. They included cough, nasopharyngitis, rhinitis and vomiting. Three children experienced serious events. However, these were related to the underlying diseases of the children and were not caused by the contrast agent.

Conclusion

The prospective trial on PK and safety data of gadobutrol in children aged under two years revealed a biodistribution of the drug similar to older patients, and a good safety profile. The authors therefore recommend the use of gadobutrol at the standard dose in children aged zero to two years.

Original Article: Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations.