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Increlex

Clinical Pharmacology
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CLINICAL PHARMACOLOGY

Increlex

General

Insulin-like growth factor-1 (IGF-1) is the principal hormonal mediator of 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 leading to 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.

Pharmacokinetics

Absorption While the bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects has been reported to be close to 100%, the absolute bioavailability of INCRELEX given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.

Distribution 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.

Metabolism Both the liver and the kidney have been shown to metabolize IGF-1.

Excretion 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 and CL/F is estimated to be 0.04 L/hr/kg at 3 mcg/mL IGFBP-3.

Summary of INCRELEX Single-Dose Pharmacokinetic
Parameters in Children with Severe Primary IGFD
(0.12 mg/kg, SC)

cmax

(ng/mL)

tmax

(hr)

AUC0-8

(hr*ng/mL)

t1/2

(hr )

Vd/F (L/kg)

CL/F

(L/hr/kg)
Brand Name: Increlex
Generic Name: Mecasermin [rDNA origin] Injection
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