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Egrifta

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Egrifta

Egrifta

CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro, tesamorelin binds and stimulates human GRF receptors with similar potency as the endogenous GRF.

Growth Hormone-Releasing Factor (GRF), also known as growth hormone-releasing hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. GH exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.

Pharmacodynamics

Effects on IGF-1 and IGFBP-3 levels

Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels [see Clinical Studies].

Other Pituitary Hormones

No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH) and prolactin, were observed in subjects receiving EGRIFTA™ in Phase 3 clinical trials.

Pharmacokinetics

Absorption

The absolute bioavailability of EGRIFTA™ after subcutaneous administration of a 2 mg dose was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics of EGRIFTA™ have been characterized in healthy subjects and HTV-infected patients without lipodystrophy following 2 mg subcutaneous administration.

The mean values [coefficient of variation (CV)] of the extent of absorption (AUC) for tesamorelin were 634.6 (72.4) and 852.8 (91.9) pg.h/mL in healthy subjects and HTV-infected patients, respectively, after a single subcutaneous administration of a 2 mg EGRIFTA™ dose. The mean (CV) peak tesamorelin concentration (Cmax) values were 2874.6 (43.9) pg/mL in healthy subjects and 2822.3 (48.9) pg/mL in HTV-infected patients. The median peak plasma tesamorelin concentration (Tmax)was 0.15 h in both populations.

Distribution

The mean volume of distribution (±SD) of tesamorelin following a single subcutaneous administration was 9.4±3.1 L/kg in healthy subjects and 10.5±6.1 L/kg in HTV-infected patients.

Metabolism

No formal metabolism studies have been performed in humans.

Elimination

Mean elimination half-life (T1/2) of tesamorelin was 26 and 38 minutes in healthy subjects and HTV-infected patients, respectively, after subcutaneous administration for 14 consecutive days.

Drug Interactions

Simvastatin

The effect of multiple dose administration of EGRIFTA™ (2 mg) on the pharmacokinetics of simvastatin and simvastatin acid was evaluated in healthy subjects. Co-administration of EGRIFTA™ and simvastatin (a sensitive CYP3A substrate) resulted in 8% decrease in extent of absorption (AUCinf) and 5% increase in rate of absorption (Cmax) of simvastatin. For simvastatin acid there was a 15% decrease in AUCinf and 1% decrease in Cmax [see DRUG INTERACTIONS].

Ritonavir

The effect of multiple dose administration of EGRIFTA™ (2 mg) on the pharmacokinetics of ritonavir was evaluated in healthy subjects. Co-administration of EGRIFTA™ with ritonavir resulted in 9% decrease in AUCinf and 11% decrease in Cmax of ritonavir [see DRUG INTERACTIONS].

Specific Populations

Pharmacokinetics of tesamorelin in patients with renal or hepatic impairment, in pediatric patients, or in elderly patients has not been established.

Clinical Studies

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HTV-infected patients with lipodystrophy and excess abdominal fat (abdominal lipohypertrophy). Both studies (Study 1 and 2) consisted of a 26-week Main Phase and a 26-week Extension Phase. Main inclusion criteria were age 18-65 years, a waist circumference ≥ 95 cm (37.4 inches) and a waist-to-hip ratio ≥ 0.94 for men and ≥ 94 cm (37.0 inches) and ≥ 0.88 for women, respectively, and fasting blood glucose (FBG) < 150 mg/dL (8.33 mmol/L). Main exclusion criteria included BMI ≤ 20 kg/m2, type 1 diabetes, type 2 diabetes, if previously treated with insulin or with oral hypoglycemic or insulin-sensitizing agents, history of malignancy, and hypopituitarism. Patients were on a stable anti-retroviral regimen for at least 8 weeks prior to randomization. Patients meeting the inclusion/exclusion criteria were randomized in a 2:1 ratio to receive 2 mg EGRIFTA™ or placebo subcutaneously daily for 26 weeks. The primary efficacy assessment for each of these studies was the percent change from baseline to Week 26 (Main Phase) in visceral adipose tissue (VAT), as assessed by computed tomography (CT) scan at L4-L5 vertebral level. Secondary endpoints included changes from baseline in patient-reported outcomes related to body image, triglycerides, ratio of total cholesterol to HDL cholesterol, IGF-1 levels, and safety parameters. Other endpoints included changes from baseline in waist circumference, abdominal subcutaneous tissue (SAT), trunk fat, and lean body mass. In both studies, EGRIFTA™ -treated patients completing the 26-week treatment period were re-randomized to blinded therapy with either daily placebo or 2 mg EGRIFTA™ for an additional 26-week treatment period (Extension Phase) in order to assess maintenance of VAT reduction and to gather long-term safety data. For inclusion in the Extension Phase studies, subjects must have completed the Main Phase with FBG ≤ 150 mg/dL.

Main Phase (Baseline to Week 26): Study 1

This study randomized 412 HlV-infected patients with lipodystrophy and excess abdominal fat to receive either EGRIFTA™ (N=273) or placebo (N=137). At baseline for the two groups combined, mean age was 48 years; 86% were male; 75% were white, 14% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 104 cm; mean hip circumference was 100 cm; mean VAT was 176 cm2; mean CD4 cell count was 606 cells/mm3; 69% had undetectable viral load ( < 50 copies/mL); and 33.7% randomized to EGRIFTA™ and 36.6% randomized to placebo had impaired glucose tolerance, while 5.6% randomized to EGRIFTA™ and 6.7 % randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 1 was 80%.

Study 2

This study randomized 404 HlV-infected patients with lipodystrophy and excess abdominal fat to receive either EGRIFTA™ (N=270) or placebo (N=126). At baseline for the two groups combined, mean age was 48 years; 84% were male; 77% were white, 12% were Black/African American, and 9% were Hispanic; mean weight was 88 kg; mean BMI was 29 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 189 cm2; mean CD4 cell count was 592 cells/mm3; 83% had undetectable viral load ( < 50 copies/mL); and 44.1 % randomized to EGRIFTA™ and 39.7% randomized to placebo had impaired glucose tolerance, while 9.3% randomized to EGRIFTA™ and 9.5 % randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 2 was 74%.

Results for the Main Phases of Studies 1 and 2 are presented in Tables 3 and 4.

Table 3: Changes from Baseline to Week 26 in Visceral Adipose Tissue (cm2) by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

MAIN PHASE (Baseline-Week 26)
  Study 1 Study 2
EGRIFTA™
(N=273)
Placebo
(N=137)
EGRIFTA™
(N=270)
Placebo
(N=126)
Baseline (cm2) 178 (77) 171 (77) 186(87) 195 (95)
Change (cm2) -27 4 -21 -0
Mean treatment difference (95% CI) -31 (-39,-24) -21 (-29.-12)
Mean change (%)1 -18 2 -14 -2
Mean treatment difference (95% CI)1 -20 (-24, -15) -12 (-16, -7)
Baseline data are expressed as mean (SD); Change refers to least-squares means (LSM); CI: confidence interval.
1 Results derived from the statistical model: Ln(VAT Week 26/VAT Baseline) = Ln(VAT Baseline) + treatment group

Table 4: Changes from Baseline to Week 26 in IGF-1, IGFBP-3, Weight, and Waist Circumference by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

MAIN PHASE (Baseline-Week 26)
    Study 1 Study 2
EGRIFTA™
(N=273)
Placebo
(N=137)
EGRIFTA™
(N=270)
Placebo
(N=126)
IGF-1 (ng/mL) Baseline 161 (59) 168 (75) 146 (66) 149 (59)
Change 107 -15 108 3
Mean treatment difference (95% CI) 122 (101,141) 105 (85, 126)
IGFBP-3 (mg/L) Baseline 3 (1) 3 (1) 3 (1) 3 (1)
Change 0.4 -0.2 0.8 -0.0
Mean treatment difference (95% CI) 0.6 (0.5, 0.8) 0.8(0.5,1.0)
Weight (kg) Baseline 90 (14) 90 (14) 89 (14) 87 (16)
Change -0.4 0.0 0.5 0.3
Mean treatment difference (95% CI) -0.4 (-1.3, 0.5) 0.2 (-0.7, 1.3)
Waist circumference (cm) Baseline 104 (10) 105 (9) 105 (9) 105 (9)
Change -3 (5) -1 (4) -2 (5) -1 (5)
Mean treatment difference (95% CI) -2 (-2.8, -0.9) -1 (-2.5, -0.3)
Baseline data are expressed as mean (SD); Change refers to least-squares means (LSM); CI: confidence interval.

A subgroup analysis by gender showed that there were no statistical differences in the percent change from baseline in visceral adipose tissue (VAT) and IGF-1 responses, respectively, between males and females.

At Week 26, treatment with EGRIFTA™ resulted in a reduction from baseline in mean trunk fat of 1.0 kg in Study 1 and 0.8 kg in Study 2, respectively (compared with an increase of 0.4 kg in Study 1 and of 0.2 kg in Study 2, respectively, in patients receiving placebo). Treatment with EGRIFTA™ resulted in an increase from baseline in mean lean body mass of 1.3 kg in Study 1 and of 1.2 kg in Study 2, respectively (compared with a decrease of 0.2 kg in Study 1 and of 0.03 kg in Study 2, respectively, in patients receiving placebo).

On average, there were no adverse effects of EGRIFTA™ on lipids or subcutaneous adipose tissue (SAT). EGRIFTA™ did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).

Patient Reported Outcomes

Patients rated the degree of distress associated with their belly appearance on a 9-point rating scale that was then transformed to a score from 0 (extremely upsetting and distressing) to 100 (extremely encouraging). A score of 50 indicated neutral (no feeling either way). A positive change from baseline score indicated improvement, i.e., less distress.

The cumulative distribution of response (change from baseline to 26 weeks) is shown in Figure 1 for both treatment groups. A curve shifted to the right on this scale indicates a greater percentage of patients reporting improvement.

Figure 1. Cumulative Distribution of Response for Belly Appearance Distress

Cumulative Distribution of Response for Belly Appearance Distress - Illustration

Extension Phase (Weeks 26-52):

In the double-blind Extension Phase, patients on EGRIFTA™ completing the 26-week Main Phase were re-randomized to receive 2 mg EGRIFTA™ or placebo.

Study 1

This study re-randomized 207 HIV-infected patients with lipodystrophy who completed EGRIFTA™ treatment in the Main Phase to receive either EGRIFTA™ (N=154) or placebo (N=50) for an additional 26-week duration (3:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 88% were male; 78% were white, 12% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 102 cm; mean hip circumference was 100 cm; mean VAT was 145 cm2; mean CD4 cell count was 639 cells/mm3; 68% had undetectable viral load ( < 50 copies/mL); and for those EGRIFTA™ -treated patients completing the 26-week treatment period that were re-randomized to EGRIFTA™ (T-T group) or re-randomized to placebo, 36.6 % and 32.0 %, respectively, had impaired glucose tolerance, while 2.0 % re-randomized to EGRIFTA™ and 6.0 % re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 1 was 83%.

Study 2

This study re-randomized 177 HIV-infected patients with lipodystrophy who completed EGRIFTA™ treatment in the Main Phase to receive either EGRIFTA™ (N=92) or placebo (N=85) for an additional 26-week duration (1:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 90% were male; 84% were white, 9% were Black/African American, and 7% were Hispanic; mean weight was 89 kg; mean BMI was 28 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 172 cm2; mean CD4 cell count was 579 cells/mm3; 82% had undetectable viral load ( < 50 copies/mL); and for those EGRIFTA™ -treated patients completing the 26-week treatment period that were re-randomized to EGRIFTA™ (T-T group) or re-randomized to placebo, 48.9 % and 50.6 %, respectively, had impaired glucose tolerance, while 4.3 % re-randomized to EGRIFTA™ and 12.9 % re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 2 was 81%.

Results for the Extension Phases of Studies 1 and 2 are presented in Tables 5 and 6.

Table 5: Changes from Week 26 Baseline to Week 52 in Visceral Adipose Tissue (cm2) by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

EXTENSION PHASE (Week 26-52)
  Study 1 Study 2
T-T1
(Week 26-52)
(N=154)
T-P2
(Week 26-52)
(N=50)
T-T1
(Week 26-52)
(N=92)
T-P2
(Week 26-52)
(N=85)
Week 26 (cm2) 145 (72) 144 (72) 166 (89) 177 (88)
Change (cm2) 3 25 -11 24
Mean treatment difference (95% CI) -22 (-34, -10) -35 (-48, -22)
Mean change (%)1 0 22 -5 16
Mean treatment difference (95% CI)3 -17 (-24, -10) -18 (-24, -11)
Week 26 baseline data are expressed as mean (SD). Change refers to least-squares means (LSM); CI: confidence interval.
1T-T = tesamorelin for Weeks 0-26 and tesamorelin for Weeks 26-52
2T-P = tesamorelin for Weeks 0-26 and placebo for Weeks 26-52
3Results derived from the statistical model: Ln(VAT Week 52/Week 26) = Ln(Week 26 VAT) + treatment group

Figure 2. shows the percent change in VAT from baseline (Week 0) over time until 52 weeks in completer patients.

Figure 2. Percent Change from Baseline in VAT over Time

Percent Change from Baseline in VAT over Time - Illustration

Data in Figure 2 are expressed as mean values. T-T (tesamorelin to tesamorelin) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to tesamorelin for Weeks 26-52. T-P (tesamorelin to placebo) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to placebo for Weeks 26-52. P-T (placebo to tesamorelin) refers to the group of patients who received placebo for Weeks 0-26 and were switched to tesamorelin (treated open label) for Weeks 26-52.

Table 6: Changes from Week 26 Baseline to Week 52 in IGF-1, IGFBP-3, Weight, and Waist Circumference by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

EXTENSION PHASE (Weeks 26-52)
    Study 1 Study 2
T-T1
(Week 26-52)
(N=154)
T-P2
(Week 26-52)
(N=50)
T-T1
(Week 26-52)
(N=92)
T-P2
(Week 26-52)
(N=85)
IGF-1
(ng/mL)
Week 26 291 (124) 281 (105) 280 (134) 269 (110)
Change -59 -137 -25 -135
Mean treatment difference (95% CI) 78 (50, 106) 110(87,134)
IGFBP-3
(mg/L)
Week 26 3 (1) 3 (1) 3 (1) 3 (1)
Change -0.2 -0.5 -0.3 -0.9
Mean treatment difference (95% CI) 0.3 (-0.0, 0.6) 0.6 (0.3, 0.9)
Weight (kg) Week 26 89 (14) 92 (17) 89 (13) 90 (14)
Change 0.2 0.6 -0.5 0.1
Mean treatment difference (95% CI) -0.4 (-2,1) -0.6 (-2,1)
Waist circumference (cm) Week 26 101 (10) 102 (12) 101 (9) 103(11)
Change -0.2 2.4 -1.1 0.2
Mean treatment difference (95% CI) -2.6 (-4,-!) -1.3 (-2, 0)
Week 26 baseline data are expressed as mean (SD); Change refers to least-square means (LSM); CI: confidence interval.
1 T-T = tesamorelin for Week 0-26 and tesamorelin for Week 26-52
2 T-P = tesamorelin for Week 0-26 and placebo for Week 26-52

Patients treated with EGRIFTA™ for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).

There was no adverse effect of EGRIFTA™ on lipids or subcutaneous adipose tissue (SAT). EGRIFTA™ did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).

Last reviewed on RxList: 12/12/2011
This monograph has been modified to include the generic and brand name in many instances.

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