"The U.S. Food and Drug Administration today approved Dotarem (gadoterate meglumine) for use in magnetic resonance imaging (MRI) of the brain, spine and associated tissues of patients ages 2 years and older.
Dotarem is a gadolinium-based"...
- Patient Information:
Details with Side Effects
Mechanism Of Action
Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.
The following actions have been demonstrated for endogenous human IGF-1:
Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.
Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion.
The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of INCRELEX® given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.
In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an INCRELEX® dose of 0.045 mg/kg, and is estimated to increase as the dose of INCRELEX® increases.
IGF-1 is metabolized by both liver and kidney. The mean terminal t1/2 after single subcutaneous administration of 0.12 mg/kg INCRELEX® in pediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of INCRELEX® is inversely proportional to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5 micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the median IGFBP-3 in subjects with normal IGF-1 serum levels.
In children with Primary IGFD there were no apparent differences between males and females in the pharmacokinetics of INCRELEX® .
The effect of race on pharmacokinetics of INCRELEX® has not been studied.
Summary of INCRELEX® Single-Dose
Pharmacokinetic Parameters in Children with Severe Primary IGFD (0.12 mg/kg,
|Cmax (ng/mL )||Tma (hr)||AUC0-8 (hr*ng/mL )||t½(hr)||Vd/F (L/kg)||CL/F (L/hr/kg)|
|Cmax = maximum concentration; T max = time of maximum
concentration; AUC 0-8 = area under the curve; t 1/2 = half-life; Vd/F =
apparent volume of distribution; CL/F = apparentsystemic clearance; SC =
subcutaneous injection;CV% = coefficient of variation in %.
Male/female data combined, ages 12 to 22 years.
a Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and 0.12 mg/kg SC.
PK parameters based on baseline adjusted plasma concentrations.
Mean Total IGF-1
Concentration after a Single Subcutaneous Dose of INCRELEX® in
Children with Severe Primary IGFD (0.06 mg/kg and 0.12 mg/kg, n = 3 per group)
No studies have been conducted in Primary IGFD children with renal impairment.
No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic impairment.
Effects Of INCRELEX® Treatment In Children With Severe Primary Insulin-like Growth Factor-1 Deficiency (Primary IGFD)
Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX® generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were prepubertal at baseline.
Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.
Table 1: Annual Height Results by Number of Years
Treated with INCRELEX®
|Pre-Tx||Year 1||Year 2||Year 3||Year 4||Year 5||Year 6||Year 7||Year 8|
|Height Velocity (cm/yr)|
|Mean (SD)||2.8 (1.8)||8.0 (2.2)||5.8 (1.5)||5.5 (1.8)||4.7 (1.6)||4.7 (1.6)||4.8 (1.5)||4.6 (1.5)||4.3 (1.1)|
|Mean (SD) for change from pretreatment||+5.2 (2.6)||+2.9 (2.4)||+2.3 (2.4)||+1.5 (2.2)||+1.5 (1.8)||+1.5 (1.7)||+1.0 (2.1)||+0.7 (2.5)|
|P-value for change from pre-treatment1||< 0.0001||< 0.0001||< 0.0001||0.0045||0.0015||0.0009||0.0897||0.3059|
|Height Velocity SDS|
|Mean (SD)||-3.3 (1.7)||1.9 (3.0)||-0.2 (1.6)||-0.2 (2.0)||-0.7 (2.1)||-0.6 (2.1)||-0.4 (1.4)||-0.4 (1.9)||-0.4 (1.9)|
|Mean (SD) for change from pretreatment||+5.2 (3.1)||+3.1 (2.3)||+2.9 (2.3)||+2.2 (2.2)||+2.5 (2.2)||+2.7 (1.7)||+2.5 (2.1)||+2.7 (2.8)|
|Mean (SD)||-6.7 (1.8)||-5.9 (1.8)||-5.6 (1.8)||-5.4 (1.8)||-5.5 (1.9)||-5.6 (1.8)||-5.4 (1.8)||-5.2 (2.0)||-5.2 (2.0)|
|Mean (SD) for change from pretreatment||+0.8 (0.5)||+1.2 (0.8)||+1.4 (1.1)||+1.3 (1.2)||+1.4 (1.3)||+1.4 (1.2)||+1.4 (1.1)||+1.5 (1.1)|
|Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS =
Standard Deviation Score
1 P-values for comparison versus pre-treatment values are computed using paired t-tests.
Forty-nine subjects were included in an analysis of the effects of INCRELEX® on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.
Last reviewed on RxList: 6/16/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Increlex Information
Report Problems to the Food and Drug Administration
Find out what women really need.