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Iplex

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Iplex

CLINICAL PHARMACOLOGY

The primary pharmacologic effect of IGF-1 in children is the promotion of linear growth. Secondary pharmacologic actions of IGF-1 include other anabolic effects, insulin sensitization, and insulin-like effects. There are no known direct growth-promoting effects of IGFBP-3. The primary effect of IGFBP-3 in the mecasermin rinfabate complex is the modulation of IGF-1 action.

In normal human circulation, less than 2% of total IGF-1 exists in the free form. Most circulating IGF-1 is found in association with the growth hormone (GH)-dependent binding protein IGFBP-3, and this binary complex further associates with a third serum protein, the GH-dependent acid-labile subunit (ALS), to form a non-covalent ternary complex of ~150 kD, which represents the natural physiologic reservoir of IGF-1. The ternary complex consists of one molecule each of IGF-1, IGFBP-3, and ALS.

The half-life of IGF-1 in the ternary complex is > 12 hr. Proteolytic cleavage of IGFBP-3 and interaction of the ternary complex with proteoglycans have been shown to release IGF-1 from the ternary complex.

Pharmacokinetics

In pediatric patients with severe primary IGF-1 deficiency (Primary IGFD), 1 mg/kg was administered by subcutaneous injection to 4 patients in a pharmacokinetic sub-study of the clinical trial. A summary of the pharmacokinetic parameters for IGF-1 and IGFBP-3, uncorrected for baseline values, is presented in Table 1 and Figure 1. The assays employed do not distinguish between exogenous and endogenous IGF-1 or IGFBP-3.

Table 1. Mean (±SD) Pharmacokinetic Parameters in Patients with Primary IGFD Treated with IPLEX (mecasermin rinfabate [rdna origin] injection) 1 mg/kg (n= 4)

  Cmax
(ng/mL)
Tmax
(hr)
AUC0-60
(ng hr/mL)
Half-life
(hr)
IGF-1 133±19 11.3±6.2 3654±237 13.4±2.7
IGFBP-3 1574±401 19.5±9.0 62525±8352 54.1±31.6

Figure 1. Mean (±SD) Uncorrected IGF-1 (Panel A) and IGFBP-3 (Panel B) (ng/mL) Concentrations in Patients with Primary IGFD Treated with IPLEX (mecasermin rinfabate [rdna origin] injection) 1 mg/kg (n=4)

Mean (±SD) Uncorrected IGF-1 (Panel A) - Illustration

Mean (±SD) Uncorrected IGF-1 IGFBP-3 (Panel B) - Illustration

Special Populations

Geriatric

The pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) have not been studied in subjects greater than 65 years of age.

Gender

No information is available.

Race

No information is available.

Renal insufficiency

No studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) .

Hepatic insufficiency

No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) .

Clinical Studies

A prospective, open-label multicenter study was conducted to evaluate the safety and efficacy of IPLEX (mecasermin rinfabate [rDNA origin] injection) in children and adolescents with primary IGF-1 deficiency (Primary IGFD). Subjects were enrolled in the clinical trial on the basis of extreme short stature, low IGF-1 and IGFBP-3 serum concentrations, and normal GH secretion. Thirty-six prepubertal subjects received up to 2 mg/kg mecasermin rinfabate administered once daily by subcutaneous injection for a mean duration of 10.4 months (range: 27 days – 22.5 months). Baseline characteristics at enrollment were (mean ± standard deviation [SD]): chronological age (years): 8.7± 3.1; bone age (years): 5.9 ± 3.2 (n=27); height standard deviation score (SDS): -6.9 ± 1.7; height velocity (cm/yr): 3.0 ± 1.8. Thirty-two (89%) had Primary IGFD due to GH receptor deficiency (Laron syndrome), 3 (8%) had GH gene deletion with neutralizing antibodies to GH, and one (3%) had Primary IGFD due to unknown etiology. Twenty (56%) of the subjects were male and 28 (78%) were Caucasian. All subjects were prepubertal at baseline.

Subjects were divided into two cohorts treated sequentially: Cohort # 1 (n=19) and Cohort # 2 (n=17). Treatment was initiated at a dose of 0.5 mg/kg daily and titrated upward to a maximum dose of 2 mg/kg/day based on clinical tolerability and serum IGF-1 levels. In Cohort #1, subjects were treated with a dose of up to 1 mg/kg daily for the first 12 months; 16 subjects were evaluable for efficacy at Month 6 and Month 12. Subjects in Cohort # 2 were titrated up to 2 mg/kg daily; 9 subjects were evaluable for efficacy at Month 6. Primary and secondary efficacy endpoints are summarized in Table 2. Efficacy beyond one year of treatment has not been established.

Table 2. Mean (± SD) Efficacy Results for Patients with Primary IGFD Treated with Mecasermin Rinfabate

Endpoint Cohort #1 ( ≤ 1 mg/kg daily) [1] Cohort #2
( ≤ 2 mg/kgdaily) [2]
Pre-Tx
(n=16)
Month 6
(n=16)
Month 12
(n=16)
Pre-Tx
(n=9)
Month 6
(n=9)
Annualized Height Velocity (cm/yr) 3.4 ± 1.9 7.4 ± 2.0 6.4 ± 1.6 2.2 ± 1.5 8.8 ± 2.0
Change in Height Velocity from Pre-Tx (cm/yr)   4.0 ± 1.8 3.0 ± 1.3   6.6 ± 2.6
p-value for Change in Height Velocity from Pre-Tx [3]   < 0.0001 < 0.0001   < 0.0001
Height SDS -6.4 ± 2.1 -6.1 ± 2.1 -6.0 ± 2.2 -7.9 ± 1.1 -7.5 ± 1.1
Change in Height SDS from Pre-Tx   0.3 ± 0.2 0.5 ± 0.4   0.4 ± 0.3
p-value for Change in Height SDS from Pre-Tx [3]   < 0.0001 < 0.002   < 0.001
Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score.
[1] Mean Month 0-6 dose: 0.96 mg/kg daily.
[2] Mean Month 0-6 dose: 1.4 mg/kg daily.
[3] Paired t-test or Wilcoxon signed rank test

In the Cohort #1 evaluable population, there were 10 subjects with detectable acid-labile subunit (ALS) levels and 6 subjects with undetectable ALS. The mean height velocity for Months 0-6 was 8.1 ± 2.2 cm/yr for Cohort #1 subjects with detectable ALS and 6.3 ± 1.0 cm/yr for Cohort #1 subjects with undetectable ALS levels. In the Cohort #2 evaluable population, 8/9 subjects had undetectable ALS, and had a mean height velocity for Months 0-6 of 9.1 ± 1.9 cm/yr on the higher dose. In Cohort #1, height velocity correlated with IGF-1 SDS at Month 1 (r=0.71, p=0.005, n=14). The mean height velocity for Month 0-6 was 8.5 ± 2.1 cm/yr for subjects with IGF-1 SDS at Month ≥ 1 -2 (n=8), and 6.7 ± 1.2 cm/yr for subjects with IGF-1 SDS at Month 1 < -2 (n=6).

Last reviewed on RxList: 3/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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