Results
Subjects
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 (%)
Male 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.
Safety
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)
Overall 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
Investigations
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
Dizziness 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.
Discussion
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 others
12,
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.
Conclusions
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.
Acknowledgments
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.
References
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