This study shows how much your GH and IGF-1 should rise after a 4 mg GH injection

Discussion in 'Steroid Lab Testing' started by master.on, Nov 29, 2018.

  1. master.on

    master.on Member

    They first used a drug called ocreotide to suppress natural GH to avoid confusion. 4 mg GH was injected, blood was drawn every hour for 24 hours to determine GH and igf-1 levels.

    In short, after a 4 mg (12 IU) subcutanueous GH injection
    their GH blood levels peaked about 4.72 hours after injection (Tmax), with a maximum concentration of 52.97 ng/ml
    their IGF-1 blood levels peaked about 23.37 hours after injection, with a maximum median concentration of 97.43 ng/ml

    So, to test GH pin it
    get GH bloodwork about 4 hours 43 minutes
    and IGF-1 about 23 hours 22 minutes
    after pinning
    and your GH, IGF-1 values should be similar to those quoted above.

    Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects
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  2. master.on

    master.on Member

    Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects

    Darin B.BrimhallDO,FACP1 NiclasPetriPhD2 PinaD’AngeloMSc3

    Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection.

    In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle-free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin-like growth factor-1 (igf-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC0–24, AUC0–∞, Cmax, area under the effect-time curve from time 0 to 24 hours (AUEC0–24), and maximum effect concentration (Emax). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the α = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range.

    A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987–1.040) for AUC0–24, 1.012 (0.986–1.038) for AUC0–∞, and 1.200 (1.137–1.267) for Cmax. For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818–0.993) for AUEC0–24 and 0.867 (0.795–0.946) for Emax. Non–baseline-corrected values were 0.978 (0.953–1.004) for AUEC0–24 and 0.953 (0.923–0.984) for Emax. Both treatments were well tolerated; blood glucose levels increased in nearly all subjects (98.3%). All adverse events were mild and resolved spontaneously within 24 hours.

    Bioequivalence was shown for a single 4-mg dose of somatropin delivered by using a needle-free device compared with SC injection based on ln-transformed AUC0–24 and AUC0–∞ but not ln-transformed Cmax.

    Treatment with recombinant human growth hormone (rhGH) is recommended as early as possible in children diagnosed with growth hormone deficiency (GHD) to normalize height during childhood and to allow normal height to be achieved in adulthood.1 Traditionally, rhGH is administered by subcutaneous (SC) injection using a needle and syringe; however, some patients report this method of administration to be painful, increasing the potential for nonadherence.2 Needle-free devices were developed as an alternative to the needle and syringe for administration of rhGH, which has shown bioequivalence when given by either method in healthy subjects and patients with GHD.2, 3, 4

    Somatropin, a naturally occurring growth hormone (GH), is manufactured by using recombinant DNA technology to have the same amino acid sequence as the natural hormone and is marketed under multiple trade names. Zomacton is approved in the United States for the treatment of children with growth failure due to inadequate secretion of endogenous GH5 and in the European Union for the treatment of pediatric GHD and growth retardation due to Turner syndrome confirmed by chromosomal analysis.6 This somatropin formulation is administered by using a standard sterile disposable syringe or a ZomaJet needle-free injection device (Antares Pharma, Ewing, New Jersey, for Ferring Pharmaceuticals, Inc).5, 6 The ZomaJet device transjects somatropin through the epidermis and into the SC layer of the skin; with the new formulation, it allows injection of more concentrated somatropin, which lowers the injection volume by 3-fold.7

    At the time of the current study, somatropin was available in 5-mg vials for reconstitution, and a 10-mg vial of powdered somatropin for reconstitution was under development for use with the ZomaJet device. This study compared the relative bioavailability of a single 4-mg dose reconstituted from a 10-mg vial of somatropin and administered via the ZomaJet versus that of a single 4-mg dose reconstituted from a 5-mg vial and administered via a traditional SC injection.

    Subjects and Methods

    Healthy men and women aged 18 to 35 years were eligible if they had a body mass index of 19 to 30 kg/m2 and serum GH levels appropriate for their age and sex. Subjects were excluded if they had a history of allergy or sensitivity to injected proteins (or any drug hypersensitivity or allergy deemed by the investigator to potentially compromise patient safety); significant history or current evidence of chronic infectious disease, system disorder, or organ dysfunction; current abnormal medical condition (including the common cold or seasonal or chronic allergies); psychiatric disorders requiring hospitalization or medication within the last 2 years; medical conditions requiring regular treatment with prescription drugs; use of pharmacologic agents known to affect or inhibit drug-metabolizing enzymes; or history of hemophilia. Pregnant or lactating women and those of childbearing potential were also excluded.

    Subjects were not permitted any nonstudy medications after check-in at the study center. Before check-in, subjects were instructed not to use any prescription medications for 14 days or over-the-counter medications for 7 days. Tobacco products were prohibited from 90 days before dosing and throughout the study.

    Study Design
    This randomized, single-dose, crossover study was conducted from October to November 2011 at a single site in Las Vegas, Nevada. The study was conducted in accordance with ethical principles of the Declaration of Helsinki and in compliance with the US Code of Federal Regulations and International Conference on Harmonisation and Guideline for Good Clinical Practice (E6)R1, as well as the Belmont Report. The Novum Independent Institutional Review Board approved the protocol and informed consent form, and all subjects provided written informed consent before participating.

    The study consisted of 2 dosing periods separated by a 7-day washout period and compared single 4-mg doses of somatropin administered by using a needle-free device and standard SC injection. Subjects were screened for eligibility within 28 days before the first study period and were randomized to receive somatropin⁎ 4 mg reconstituted from a 10-mg vial formulation and administered via the ZomaJet needle-free device or somatropin 4 mg reconstituted from a 5-mg vial administered via SC injection† using a 30-gauge needle.8 A 4-mg dose of somatropin was selected to ensure detectable serum levels of somatropin and insulin-like growth factor-1 (IGF-1) in subjects for whom endogenous GH secretion was suppressed.9, 10

    The needle-free device and syringe were weighed before and after dosing to calculate the actual weight of study drug administered. On the day before period 1 dosing, 3 sizes of device head were tested according to the manufacturer’s instructions by administration of 0.8 mL of sterile 0.9% saline solution in the abdomen of each subject. This method ensured proper handling of and familiarity with the device and assured that the correct head size was selected for each subject. The smallest head that allowed complete injection of the saline in each subject was selected for use.

    The randomization schedule was generated in blocks of 4, using 4 sequences that took into account both treatment (A or B) and administration site (right or left abdomen) by study period. The study sequence for the 2 study periods was right A/left B, right B/left A, left A/right B, and left B/right A. The study was conducted by using multiple groups, each consisting of 11 or 12 subjects.

    To ensure that results would not be influenced by endogenous GH, octreotide acetate‡ was administered to all study subjects. A 1-mL ampule (50 µg/mL) was diluted with 9 mL of 0.9% sodium chloride to produce a final concentration of 5 µg/mL, which was administered as a slow bolus infusion over 3 minutes starting 1 hour before somatropin dosing. A maintenance dose of octreotide (1 µg/mL; 40 mL/h) was infused slowly after the bolus dose and continued for ~25 hours until the last blood sample was collected.

    Subjects entered the study site during the evening before dosing and remained until the last blood sample was collected. They received an evening meal ≥10 hours before dosing and a light breakfast ~30 minutes before the octreotide bolus infusion. Subjects fasted for ≥4 hours after each somatropin dose and then received standardized, caffeine-free meals and snacks at set meal times. No fluids other than water and beverages served with meals were allowed. Subjects were confined to bed, except as needed to go to the bathroom, starting with the bolus infusion of octreotide. Blood glucose and vital signs were monitored at bedside during and after the infusion of octreotide. Trained site personnel administered study treatments and performed all study procedures bedside.

    Assessment of Study Drug Administration
    For each dose of somatropin, leakage at the administration site was assessed by using a rating scale with scores as follows: 1 = all of the injectable solution penetrated the skin; 2S = slight wetness on the skin (mist); 2 = most of the injectable solution penetrated the skin (only a pinhead-sized drop did not); 3 = about one half of the injectable solution penetrated the skin; and 4 = little or no injectable solution penetrated the skin. Subjects with scores of 3 or 4 after injection were discontinued from the study.

    Pharmacokinetic/Pharmacodynamic Assessments
    Blood samples (10 mL) were collected for determination of somatropin and IGF-1 concentrations in red-top serum collection tubes (containing no anticoagulant) at 30 minutes before somatropin dosing; within 5 minutes before dosing; and at 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 16, and 24 hours after dosing. The samples were allowed to clot at room temperature for ≥30 minutes and then centrifuged at 3000 rpm for 10 minutes at 4°C. Each serum sample was divided into 4 aliquots and frozen at −80°C in polypropylene tubes. The serum samples were shipped overnight on dry ice to PharmaNet USA, Inc (Princeton, New Jersey), and stored frozen until analysis. Serum somatropin and IGF-1 concentrations were analyzed by using a validated, double-antibody, sandwich ELISA with Quantikine kits (R&D Systems Inc, Minneapolis, Minnesota). The lower limit of quantitation for serum somatropin and IGF-1 was 0.3 and 31.25 ng/mL, respectively. The interbatch precision for the serum somatropin analysis has been reported by PharmaNet USA to be ≤23.1% (lower limit of quantification [standard, ≤7.67%]), with a mean bias of –3.2% to 7.0%. For the IGF-1 assay, the interbatch precision and mean bias are reportedly ≤5.6% (standard, ≤6.88%) and −14.8% to 12.9%, respectively.

    Pharmacokinetic parameters were calculated by using the proprietary software Bioequiv (versions 3.50 and 3.51; Anapharm Bioanalytics, Barcelona, Spain) and determined by noncompartmental methods. The somatropin and IGF-1 concentration–time profiles for each subject were constructed by using the actual times of sample collections. Cmax and Tmax were determined from observed data. AUC0–24 was calculated by the linear trapezoidal method. AUC0–∞ was calculated as AUC0–24 + Ct/ke, where Ct is the last measurable drug concentration; ke was estimated from the slope of the regression line for the terminal ln-transformed linear concentration–time values. The terminal t½ was calculated as ln(2)/ke. Pharmacodynamic parameters for IGF-1 included maximum effect concentration (Emax) and area under the effect-time curve from time 0 to 24 hours (AUEC0–24).

    Safety Assessment
    Adverse events (AEs) were monitored through solicited and unsolicited means coded by using the Medical Dictionary for Regulatory Activities, version 14.1. Vital signs were measured before each dose and periodically at scheduled times after dosing. A 12-lead ECG was performed within 2 hours before and 4 hours after each somatropin dose and at discharge from the center. Clinical laboratory testing was performed at screening and at discharge after the second study period.

    Statistical Analysis
    A sample size of 50 subjects completing the study was determined to have at least 90% power to show bioequivalence between the 2 somatropin treatments, assuming a 20% intrasubject %CV for the Cmax of somatropin. A sample size of 60 was planned to allow for subjects discontinuing from the study before completing both periods. All statistical and pharmacokinetic analyses were performed by using SAS version 9.2 or later (SAS Institute, Inc, Cary, North Carolina).

    Only subjects who completed both study periods were included in the pharmacokinetic and statistical analyses. All postdose serum concentrations of somatropin and IGF-1 were baseline corrected by subtracting the mean of the serum concentrations in the 2 predose samples (obtained at 30 minutes and within 5 minutes predose); any negative value after baseline correction was considered as 0. Comparisons between treatments were made by ANOVA performed by using the general linear model procedure of SAS; the model included effects of group, sequence, subject nested within group-by-sequence, group-by-sequence, treatment, and period nested within group. The group-by-treatment interaction was tested before pooling the data across groups. The least squares (LS) means for each treatment were determined. The 90% CIs of the geometric mean ratios of the LS means for the test (needle-free device) compared with the reference (SC injection) were constructed to test two 1-sided hypotheses at the α = 0.05 level for AUC0–24, AUC0–∞, Cmax, AUEC0–24, and Emax. The determination of bioequivalence was based on ln-transformed data for somatropin. Bioequivalence was concluded if the 90% CIs for the major pharmacokinetic/pharmacodynamic parameters fell within the 80% to 125% acceptance range.11 AEs were analyzed descriptively.
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  3. master.on

    master.on Member

    A total of 59 subjects were enrolled; 1 subject was discontinued after somatropin dosing in period 1 because of injection site leakage (score = 3), and 1 subject was discontinued by the investigator at the check-in for period 2 for noncompliance with study procedures. The remaining 57 subjects completed both study periods and were included in the pharmacokinetic analyses. The pharmacokinetic cohort had a median age of 28 years (range, 18–35 years); 75.4% were men (Table I). Safety was evaluated for 58 subjects dosed in each study period.

    Table I
    Characteristic Value
    Age, y
    Mean (SD)
    27.2 (4.86)
    Median (range) 28.0 (18–35)
    Sex, n (%)
    43 (75.4)
    Female 14 (24.6)
    Race, n (%)
    American Indian or Alaskan Native
    2 (3.5)
    Asian 3 (5.3)
    Black or African American 21 (36.8)
    Native Hawaiian or Pacific Islander 2 (3.5)
    White 11 (19.3)
    Other 18 (31.6)
    Ethnicity, n (%)
    Hispanic or Latino
    20 (35.1)
    Not Hispanic or Latino 37 (64.9)
    Weight, kg
    Mean (SD)
    75.8 (12.84)
    Median (range) 75.7 (47–105)
    Body mass index, kg/m2
    Mean (SD)
    25.0 (3.15)
    Median (range) 24.9 (19.2–29.9)
    Pharmacokinetic Parameters
    Needle-free administration of somatropin with the ZomaJet device resulted in an earlier peak concentration than SC injection, with a mean (SD) Cmax of 62.1 (17.5) ng/mL and a median Tmax of 3.0 hours (Table II). After SC injection of somatropin, mean Cmax values of 53.0 (18.9) ng/mL were observed at a median Tmax of 4.0 hours. Total exposure was comparable after needle-free and SC administration, with AUC0–∞ values of 427.82 (86.39) ng·h/mL) and 424.78 (94.99) ng·h/mL, respectively, indicating a complete administration with the needle-free device. Subjects were fully suppressed and did not display detectable endogenous levels of GH at the time of treatment administration, and results were not dependent on residual baseline measurements. Somatropin displayed first-order elimination and a t½ of ~2.7 hours with the needle-free device and 2.8 hours with SC injection (Figure 1).

    Table II
    Parameter Needle-Free Device SC Injection
    Mean (SD)*
    %CV Mean (SD)* %CV
    AUC0–24, ng·h/mL
    420.42 (85.58) 20.36 416.53 (93.04) 22.34
    AUC0–∞, ng·h/mL 427.82 (86.39) 20.19 424.78 (94.99) 22.36
    Cmax, ng/mL 62.12 (17.47) 28.13 52.97 (18.89) 35.66
    Tmax, h 3.02 (0.82) 27.05 4.72 (1.34) 28.29
    ke, 1/h 0.266 (0.054) 20.36 0.262 (0.061) 23.15
    t½, h 2.71 (0.51) 18.66 2.80 (0.70) 25.12

    SC = subcutaneous.

    Arithmetic mean using untransformed data.

    Median Tmax, 3 hours.

    Median Tmax, 4 hours.

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    Figure 1
    The geometric mean ratios for ln-transformed AUC0–24 and AUC0–∞ were 1.013 (90% CI, 0.987–1.040) and 1.012 (90% CI, 0.986–1.038), respectively (Table III). For both parameters, the 90% CIs fell within the acceptance range of 0.800 to 1.250 for bioequivalence. For ln-transformed Cmax, the geometric mean ratio was 1.200 (90% CI, 1.137–1.267); the upper bound of the 90% CI was just above the upper bound of the acceptance range for bioequivalence.

    Table III
    Parameter Geometric Mean Geometric Mean Ratio 90% CI* Intrasubject %CV
    Needle-Free Device
    Standard SC Injection
    AUC0–24, ng·h/mL
    409.81 404.50 1.0131 0.987–1.040 8.46
    AUC0–∞, ng·h/mL 417.24 412.46 1.0116 0.986–1.038 8.14
    Cmax, ng/mL 59.04 49.18 1.2004 1.137–1.267 17.36

    SC = subcutaneous.

    Bioequivalent if CIs are within 0.800 to 1.250 (80%–125%) bounds.

    Pharmacodynamic Parameters
    Blood draws for serum igf-1 concentrations were performed over 24 hours after somatropin administration, when subjects had suppressed endogenous levels of GH. The IGF-1 levels increased progressively after administration of somatropin, and a partial area of the full response was captured (Figure 2). Needle-free and SC treatments had overlapping responses over the 24 hours with maximal response, with an Emax of 242.7 and 254.7 ng/mL and an AUEC0–24 of 4674.2 and 4771.5 ng·h/mL, respectively. Baseline-corrected mean (SD) values for the IGF-1 AUEC0–24 were 962.1 (425.6) and 1042.2 (412.9) ng·h/mL after somatropin dosing via the needle-free device and SC injection, respectively (Table IV). Respective mean IGF-1 Emax values were 85.2 and 97.4 ng/mL. In the ANOVA model using baseline-corrected ln-transformed values, the 90% CI of the geometric mean ratio for IGF-1 AUEC0–24 fell within the acceptance range for bioequivalence (Table V). For IGF-1 ln-transformed Emax, the lower bound of the 90% CI fell just below the acceptance range. The 90% CIs for both parameters fell into the acceptance range for bioequivalence using the non–baseline-corrected values.

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    Figure 2
    Table IV
    Parameter Needle-Free Device SC Injection
    Mean (SD)
    %CV Mean (SD) %CV
    Arithmetic mean of untransformed data
    AUEC0–24, ng·h/mL
    962.08 (425.58) 44.24 1042.24 (412.89) 39.62
    Emax, ng/mL 85.15 (36.76) 43.18 97.43 (42.12) 43.23
    Tmax, h 21.90 (4.01) 18.30 23.37 (2.37) 10.12
    Untransformed, non–baseline-corrected values
    AUEC0–24, ng·h/mL
    4674.24 (NA) 69.85 4771.51 (NA) 68.59
    Emax, ng/mL 242.74 (NA) 71.68 254.66 (NA) 71.59

    Emax = maximum effect concentration; NA = not available; SC = subcutaneous.

    Table V
    Parameter Geometric Mean Geometric Mean Ratio 90% CI* Intrasubject %CV
    Needle-Free Device
    SC Injection
    ANOVA of ln-transformed values
    AUEC0–24, ng·h/mL
    852.76 946.64 0.901 0.818–0.993 31.56
    Emax, ng/mL 77.08 88.90 0.867 0.795–0.946 28.14
    ln-transformed, non–baseline-corrected values
    AUEC0–24, ng·h/mL
    4614.64 4717.00 0.978 0.953–1.004 8.34
    Emax, ng/mL 239.16 250.91 0.953 0.923–0.984 10.27
    ANOVA of untransformed values
    AUEC0–24, ng·h/mL
    969.19 1048.90 0.9240 0.8561–0.9919 NA
    Emax, ng/mL 85.93 98.15 0.8755 0.8024–0.9486 NA

    Emax = maximum effect concentration; NA = not assessed; SC = subcutaneous.

    Bioequivalent if CIs are within 0.800 to 1.250 (80%–125%) limits.

    AEs were reported for 57 (98.3%) of 58 subjects who received somatropin by using the needle-free device and 57 (98.3%) of 58 subjects who received somatropin via SC injection. All AEs were mild and resolved before study completion. The most common AEs after somatropin administration via the needle-free device or SC injection were increased blood glucose levels (n = 57 for each treatment + octreotide [98.3%]), headache (n = 3 [5.2%] and n = 6 [10.3%], respectively), and upper abdominal pain (n = 3 [5.2%] and n = 4 [6.9%]) (Table VI). Twenty-six (44.1%) of the 59 subjects who received octreotide had AEs before somatropin dosing; the most common were nausea (n = 17 [28.8%]), dysgeusia (n = 5 [8.5%]), and decreased blood glucose level (n = 4 [6.8%]). All AEs reported after octreotide treatment were mild and resolved spontaneously before study completion.

    Table VI
    Adverse Event Needle-Free Device (N = 58) Needle-Free Device + Octreotide (N = 58) SC Injection (N = 58) SC Injection + Octreotide (N = 58)
    9 (15.5) 57 (98.3) 9 (15.5) 57 (98.3)
    Gastrointestinal disorders
    Upper abdominal pain
    3 (5.2) 0 4 (6.9) 0
    Dry mouth 1 (1.7) 0 0 0
    Nausea 1 (1.7) 0 1 (1.7) 0
    Vomiting 0 0 1 (1.7) 0
    Blood glucose increased
    0 57 (98.3) 0 57 (98.3)
    Blood pressure decreased 0 1 (1.7) 1 (1.7) 0
    Heart rate decreased 1 (1.7) 0 0 0
    Nervous system disorders
    1 (1.7) 0 0 0
    Headache 3 (5.2) 0 6 (10.3) 0
    Paresthesia 1 (1.7) 0 0 0
    Respiratory, thoracic, and mediastinal disorders
    Chest discomfort
    1 (1.7) 0 0 0

    SC = subcutaneous.

    With 2 exceptions, all clinical laboratory test results for blood samples collected at the time of the last pharmacokinetic blood sample were within 20% of the laboratory’s normal reference range and not considered to be clinically significant. One subject with low but not clinically significant levels of hemoglobin and hematocrit levels at screening had clinically significant decreases in hemoglobin and hematocrit, although this subject had no symptoms or ongoing AEs at the end of the study. These findings were deemed by the investigator to be unrelated to the study drug. Efforts to contact this subject for repeat analysis were unsuccessful. Platelet count could not be assessed for another subject because of sample aggregation and loss to follow-up. Assessment of vital signs showed that 4 subjects had AEs of decreased blood pressure and 1 subject had a decreased heart rate; all were considered to be of mild severity by the study investigator and spontaneously resolved.

    In this comparison of the bioavailability of single 4-mg somatropin doses administered with the ZomaJet needle-free device versus a traditional SC injection by needle and syringe, exposure to somatropin based on the ln-transformed AUC0–24 and AUC0–∞ fell within the 80% to 125% acceptance range for bioequivalence; thus, total exposure to somatropin was bioequivalent with the needle-free device and SC injection. However, the Cmax displayed more variability, the point estimate was 20% higher after dosing with the needle-free device, and the 90% CI of the geometric mean ratio of ln-transformed Cmax was not fully contained within the acceptance range for bioequivalence, with the upper bound of 1.267 just above the upper bound of the range.

    Several previous studies evaluating earlier versions of the somatropin ZomaJet device also found AUC parameters that met bioequivalence criteria but Cmax values that were higher and earlier than with SC injection.12, 13 The AUEC0–24 and Emax for IGF-1 were reduced with the needle-free device compared with the SC injection, but for both parameters, the 90% CI fell within the acceptance range.13 In both studies, pharmacokinetic assessments were performed only over 24 hours, and notably, octreotide was not administered to suppress endogenous GH levels, which may have influenced the findings. It has been suggested that needle-free devices allow more extensive spread of the drug under the skin than SC needle injections and potentially a distribution into capillaries, which would increase the surface area available for drug uptake; this action, in turn, would allow more rapid absorption into the systemic circulation (ie, increase in Cmaxbut not AUC).12, 13 Although this hypothesis is unproven, it does not affect overall exposure to somatropin as measured by using AUC parameters. However, other studies of different somatropin needle-free devices in healthy subjects have shown bioequivalence compared with traditional SC needle injections based on both AUC and Cmax data.2, 4

    Because somatropin increases circulating IGF-1 levels, IGF-1 is the preferred pharmacodynamic measure for comparative studies of somatropin products,14 and levels have been analyzed in many other studies.3, 10, 12, 13, 15 These increases occur principally through actions in the liver, and, in turn, IGF-1 provides growth-stimulating effects on multiple target tissues.16, 17 In the current study, serum IGF-1 levels increased over the 24 hours after somatropin dosing, with serum levels remaining elevated at the last pharmacokinetic time point when serum somatropin levels had returned to baseline. Findings from the current study and others12, 13support the notion that the dynamic effects of IGF-1 are related more to the AUC than to the Emax. Using the serum IGF-1 data, the 90% CI of the geometric mean ratio for baseline-corrected ln-transformed AUEC0–24 fell within the acceptance range for bioequivalence; interestingly, the 90% CI for ln-transformed Emax had a lower bound of 0.795, just below the lower bound of the acceptance range. Bioequivalence criteria were met for AUEC0–24 and Emax if non–baseline-corrected IGF-1 values were used in the analysis, similar to previous findings in subjects without downregulated endogenous levels of GH,12, 13 as well as with other somatropin products.10, 15 In the current study, IGF-1 levels were observed only during downregulation (ie, 24 hours after somatropin administration), but compared with other studies in which IGF-1 was evaluated for 96 hours, the Tmax and non–baseline-corrected Emax corresponded well.10, 15

    The AEs observed after a single dose of somatropin in these healthy volunteers were consistent with the known safety profile of somatropin.5, 6 All AEs were mild and resolved by the end of the 24 hours of pharmacokinetic sampling. Nearly all subjects had increased glucose concentrations regardless of whether somatropin was administered via the needle-free device or SC injection. Somatropin is known to increase serum glucose levels under hypoglycemic conditions by increasing hepatic glucose production via glycogenolysis and gluconeogenesis.17 Product labeling for somatropin indicates that large doses may be associated with impaired glucose tolerance.5, 6 AEs commonly associated with octreotide include gallbladder abnormalities, sinus bradycardia, conduction abnormalities and arrhythmias, gastrointestinal issues (diarrhea, loose stools, nausea, and abdominal discomfort), and hypoglycemia and hyperglycemia,18 which are generally consistent with the common AEs observed in this study after octreotide infusion but before dosing of somatropin (ie, nausea, dysgeusia, and decreased blood glucose level).

    This study was conducted in healthy volunteers rather than in patients with GHD. Coadministration of octreotide was used to simulate conditions of GHD by suppressing endogenous somatropin production,18 as well as to minimize the influence of variability in patient characteristics on pharmacokinetic parameters, as recommended by health authorities.11However, findings in healthy adult volunteers in the current study might not be consistent with those in pediatric patients with GHD, who may have relatively greater pharmacokinetic variability because of fluctuating endogenous GH levels, underlying disease, and use of concomitant medications. There are additional limitations to the study, as the somatropin formulation administered with the needle-free device differed from that given via SC injection, as did the volume injected. The ZomaJet was designed for use with a 10-mg vial of somatropin for reconstitution, which allows delivery of a more concentrated solution in a smaller injection volume with greater precision.7 For the SC injection, the dose of somatropin was obtained from a marketed 5-mg vial for reconstitution. It is possible that the findings may have been influenced by the use of the same dose of somatropin (4 mg) administered to all subjects in this study, regardless of body weight. Somatropin is typically dosed according to body weight, with a recommended therapeutic dose of 0.1 mg/kg reconstituted in an injected volume of 1–5 mL.5 Particularly because Zomacton is indicated for use in pediatric patients,5the dosage and injection volume in this study were relatively high. However, the study showed that bioequivalence, based on AUC parameters, could be obtained despite these differences.

    Bioequivalence was demonstrated for a single 4-mg dose of somatropin delivered by using the ZomaJet needle-free device compared with a traditional SC needle injection based on ln-transformed AUC0–24 and AUC0–∞ but not based on ln-transformed Cmax. The results are also supported by the comparable IGF-1 levels for the 2 treatments. Both formulations and delivery routes were well tolerated by these healthy volunteers.

    Conflicts Of Interest
    Dr. Petri is an employee of Ferring Pharmaceuticals A/S. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

    This study was supported by Ferring Pharmaceuticals, Inc.

    The authors thank Kristen W. Quinn, PhD, of Peloton Advantage, LLC, for providing medical writing and editorial support, which was funded by Ferring Pharmaceuticals, Inc, in accordance with Good Publication Practice (GPP3) guidelines (GPP3).

    Dr. Brimhall was involved in study design, enrolled subjects, collected and assembled the data, interpreted the data, and reviewed the drafts of the manuscript; Dr. Petri was involved in study design, interpreted the data, and reviewed the drafts of the manuscript; and Ms. D’Angelo analyzed the data and reviewed the drafts of the manuscript. All authors read and approved the final version of the manuscript for publication.

  4. master.on

    master.on Member

    While 4 mg (12 IU) is too high a dose for daily use,
    you may wish to inject that much once, just to test GH potency.
    By injecting such a high dosage, you avoid being confounded by peptides, which may rise a little bit, but never as much as 4 mg GH does.
  5. TRT

    TRT Member

    So the igf-1 was 97.?
    Or are they using a different method of measurement?
  6. master.on

    master.on Member

    A median peak of 97.43 ng/ml, (a median of) 23.37 hours after injection.
  7. TRT

    TRT Member

    Isn't that shitty compared to the normal 600 you can get off of 5-7ius?
  8. rpbb

    rpbb Member Supporter

    Don't feed the troll
    TRT likes this.
  9. TRT

    TRT Member

    I notice your up when I am.
    rpbb likes this.
  10. rpbb

    rpbb Member Supporter

    Been getting you at 5am my whole life.
    TRT likes this.
  11. TRT

    TRT Member

    I was too but now I'm 6am.
  12. master.on

    master.on Member

    Is that 600 in ng/ml ?
    How long after pinning do you guys get 600?
  13. JJ14

    JJ14 Junior Member

    4 weeks
  14. master.on

    master.on Member

    That's 600 ng/ml after injecting 5-7 IUs every single day for 4 weeks, isn't it?

    This study different, this one determines GH, igf-1 after a single (one time) injection.
    jaymaximus and TRT like this.
  15. TRT

    TRT Member

    Oh ya and 24hrs after injection I see. Ok. My bad. That's the second time I've done that in the last week here.