Gadavist (Page 5 of 11)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:

Differences in proton density
Differences of the spin-lattice or longitudinal relaxation times (T1 )
Differences in the spin-spin or transverse relaxation time (T2 )

When placed in a magnetic field, Gadavist shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Gadavist, is based upon several factors including the concentration of Gadavist in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1 -weighted magnetic resonance sequences. In T2 *-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

12.2 Pharmacodynamics

Gadavist leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1 ) — determined from the influence on the relaxation times (T1 ) of protons in plasma — is 5.2 L/(mmol·sec) and the relaxivity (r2 ) — determined from the influence on the relaxation times (T2 ) — is 6.1 L/(mmol·sec). These relaxivities display only slight dependence on the strength of the magnetic field. The T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization.

Table 3: Relaxivity (r1) of Gadolinium Chelates at 1.5 T

Gadolinium-Chelate

r1 (L·mmol -1 ·s-1)

Gadobenate

6.3

Gadobutrol

5.2

Gadodiamide

4.3

Gadofosveset

16

Gadopentetate

4.1

Gadoterate

3.6

Gadoteridol

4.1

Gadoversetamide

4.7

Gadoxetate

6.9

r1 relaxivity in plasma at 37°C

Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist results in half the volume of administration and a more compact contrast bolus injection. At the site of imaging, the relative height and width of the time intensity curve for Gadavist varies as a function of imaging location and multiple patient, injection, and device-specific factors.

Gadavist is a water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006.

12.3 Pharmacokinetics

Distribution

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].

Metabolism

Gadobutrol is not metabolized.

Elimination

Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.

Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration.

Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible.

Specific Populations

Gender

Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol.

Geriatric

A single IV dose of 0.1 mmol/kg Gadavist was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects [see Use in Specific Populations (8.5)].

Pediatric

The pharmacokinetics of gadobutrol were evaluated in two studies in a total of 130 patients age 2 to less than 18 years and in 43 patients less than 2 years of age (including term neonates). Patients received a single intravenous dose of 0.1 mmol/kg of Gadavist. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to less than 18 year old age group).

Table 4: Pharmacokinetics by Age Group (Median [Range])

0 to < 2 years

2 to 6 years

7 to 11 years

12 to < 18 years

Adults

N=43

N=45

N=39

N=46

N=93

AUC (µmolxh/L)

781

[513, 1891]

846

[412, 1331]

1025

[623, 2285]

1237

[946, 2211]

1072

[667, 1992]

CL (L/h/kg)

0.128

[0.053, 0.195]

0.119

[0.080, 0.215]

0.099

[0.043, 0.165]

0.081

[0.046, 0.103]

0.094

[0.051, 0.150]

t1/2 (h)

2.91

[1.60, 12.4]

1.91

[1.04, 2.70]

1.66

[0.91, 2.71]

1.68

[1.31, 2.48]

1.80

[1.20, 6.55]

C20 (µmol/L)

367

[280, 427]

421

[369, 673]

462

[392, 760]

511

[387, 1077]

441

[281, 829]

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