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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0514
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 2926-2930
Copyright © 2006 by The Endocrine Society

Comparative Pharmacokinetics and Pharmacodynamics of a New Sustained-Release Growth Hormone (GH), LB03002, Versus Daily GH in Adults with GH Deficiency

Martin Bidlingmaier, John Kim, Conrad Savoy, Myung J. Kim, Nils Ebrecht, Stephan de la Motte and Christian J. Strasburger

Medizinische Klinik–Innenstadt, Ludwig-Maximilians Universität (M.B., N.E.), D-80336 Munich, Germany; LG Life Sciences (J.K., M.J.K.), Seoul 150-721, Korea; BioPartners GmbH (C.S.), 6340 Baar, Switzerland; Harrison Clinical Research (S.d.l.M.), D-80636 Munich, Germany; and Charite Universitätsmedizin (C.J.S.), D-10117 Berlin, Germany

Address all correspondence and requests for reprints to: Martin Bidlingmaier, M.D., Medizinische Klinik–Innenstadt, Ludwig-Maximilians-Universität, Ziemssenstrasse 1, 80336 Munich, Germany. E-mail: martin.bidlingmaier{at}med.uni-muenchen.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: LB03002 is a novel sustained-release GH preparation administered once weekly.

Objective: Our objective was to examine the pharmacokinetics, pharmacodynamics, and safety of LB03002 vs. daily GH.

Design and Setting: This open-label, crossover study compared the pharmacokinetics and pharmacodynamics of LB03002 and daily GH.

Patients and Other Participants: Six male and three female patients with adult GH deficiency participated in the single-center study.

Intervention: Subjects were on stable daily GH treatment before the study. After a 4-wk washout with no GH, five weekly doses of LB03002 were given.

Main Outcome Measure: GH and IGF-I concentrations were measured during the last dose of daily GH and during the first and fifth weekly doses of LB03002.

Results: The observed maximal serum GH concentration was approximately doubled after LB03002 (6.1 ± 3.2 and 4.5 ± 2.2 µg/liter at first and fifth doses) compared with daily GH (2.7 ± 2.2 µg/liter). A sustained increase in GH concentration for more than 48 h was observed with LB03002, such that dose-normalized area under the curve (AUC) was not significantly different between daily GH and LB03002. Mean maximal serum IGF-I concentration was 34–41% greater with LB03002 than with daily GH, and AUC was 7-fold greater. However, normalized to GH dose, AUC for IGF-I was comparable. Adverse events and local reactions were acceptable, and there were no evident safety concerns with LB03002.

Conclusions: Multiple weekly doses of LB03002 appeared safe and well tolerated. Comparable GH bioavailability and sustained IGF-I elevations support the use of once-weekly LB03002 to replace daily GH therapy.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
RECOMBINANT HUMAN GH was introduced in 1985 for the treatment of children with growth failure (1). It was subsequently recognized that GH is not required only in childhood, and treatment of GH-deficient adults is now an additional indication for use (2). Thus, GH treatment may be necessary throughout life, similar to replacement therapies for other hormone deficiencies. GH therapy is currently recommended as daily sc injections (1, 2), which may be inconvenient and distressing for patients. The efficacy of daily therapy has been established in promoting longitudinal growth in children (3, 4) and normalization of body composition and other abnormalities resulting from the adult GH deficiency (AGHD) (5, 6). The daily dose required by GH-deficient adults on long-term treatment varies among patients because it is age and gender related (7); the dose is titrated according to the serum IGF-I level, because this is a suitable surrogate parameter for both efficacy and tolerability (2, 7, 8, 9).

Although GH is currently administered once daily, data in humans have suggested that the GH pattern has little effect on the outcome of replacement treatment, and various regimens such as intermittent administration or continuous infusion have been suggested (10, 11). Recently, safety and efficacy of a long-acting sustained formulation of GH was demonstrated at doses higher than the dose used in this study (12), although it was commercially discontinued. Sustained-release formulations of GH, which require fewer administrations than standard GH preparations, are under development and may offer a more convenient and preferable alternative to a daily injection regime. LB03002 is an injectable, sustained-release GH suspension of microparticles, consisting of GH incorporated into sodium hyaluronate, which are dispersed in an oil base of medium-chain triglycerides before injection (13). This study was carried out to examine the pharmacokinetics, pharmacodynamics, and safety of LB03002 given once weekly, at doses based on previous daily GH dose, in AGHD.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

This was a single-center, open-label, crossover, pharmacokinetics and pharmacodynamics study conducted on male and female patients with a clinical history of AGHD, either childhood or adult onset. Informed consent was obtained from all participants, and the study was conducted in accordance with the Declaration of Helsinki and with the approval of the relevant local ethical committees. Participants were adults, aged 44–65 yr, with GH deficiency diagnosed from a serum GH peak of less than 3.0 µg/liter in an insulin tolerance test and an independent second standard GH stimulation test (arginine or arginine plus GHRH), consistent with the GH Research Society guidelines (2). At study entry, all patients had been treated with stabilized daily GH injections, with no dose modifications for at least 3 months, and were serum negative for anti-GH antibodies. Exclusion criteria included major clinical conditions such as diabetes mellitus, hypertension, significant laboratory abnormalities, conditions or medications that could influence drug absorption, metabolism, or excretion, benign intracranial hypertension, renal impairment, active malignancy, or concurrent antitumor therapy.

Nine patients, six males and three females, were included in the study. Their mean (± SD) age was 55.9 ± 7.0 yr, ranging from 44–65 yr; mean weight was 88.8 ± 10.9 kg and height was 169 ± 6.4 cm. All patients had at least one other anterior pituitary hormone deficiency, treated with stable replacement therapy for at least 4 months. Male subjects also had secondary hypogonadism and were on testosterone enanthate replacement therapy. The regimen was stable for at least 6 months before and maintained throughout the study. Two of three women were on estrogen replacement therapy (estradiol). The third female patient was not on estrogen therapy. L-T4 was administered to seven patients, hydrocortisone to six patients, and desmopressin to four patients.

Study design

At entry to the study, patients continued their established therapy of GH use for 1 wk. The last GH injection at the end of this week was administered by study personnel in the clinic, and serum samples were taken to assess the pharmacokinetics and pharmacodynamics profiles. Patients then underwent a 4-wk washout period, during which no GH was administered. At the end of the washout period, all patients started LB03002 treatment.

LB03002 was supplied as a dry powder form that was dispersed in medium-chain triglycerides at a concentration of 10 mg/ml. The LB03002 was given once a week by sc injection in the abdominal area, over a 5-wk period; injections were administered by study personnel when patients attended weekly clinic visits. The weekly dose of LB03002 was based on the daily GH dose during the 3-month period before starting the washout period.

The pharmacokinetics and pharmacodynamics profile of GH was evaluated after the first and last (fifth) injections of LB03002. Safety was assessed from reporting of adverse events and from inspection of the injection site for local tolerability.

Pharmacokinetics/pharmacodynamics assays

All GH assays and measurements for pharmacodynamics profiles were determined at a single laboratory (Neuroendocrine Laboratories, Medizinische Klinik–Innenstadt, Ludwig-Maximilians Universität, Munich, Germany). Serum samples for pharmacokinetics profiles were taken at 0, 1, 2, 3, 4, 6, 9, 12, 15, and 24 h after the daily GH injection and at the same times, but omitting the 2- and 4-h samples, after the first and fifth LB03002 injections. GH levels were determined by a sandwich immunochemiluminometric assay (ICMA) (Nichols Advantage; Nichols Diagnostics Institute, San Clemente, CA); the limit of quantification (LOQ) with this assay was 0.2 µg/liter. In addition, GH was measured using the immunofunctional assay (IFA) as described previously (14), an assay that recognizes only those GH molecules that retain two intact binding sites for the GH receptor and thus can be expected to be biologically active. Therefore, the ratio IFA/ICMA was calculated to compare bioactivity of GH between the daily and sustained-release treatments.

Pharmacodynamics assessments comprised serum concentrations of IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein (GHBP), and acid-labile subunit (ALS). IGF-I determinations used a chemiluminescent two-site assay (Nichols Advantage; Nichols Diagnostics), and IGFBP-3 was measured by an ELISA (DSL-ELISA; Diagnostic Systems Laboratories, Webster, TX).

Serum ALS levels were measured in duplicate by a sandwich immunometric assay using monoclonal antibodies directed against specific N- and C-terminal oligopeptides (15). To optimize immunorecognition, samples were pretreated with 3 M urea and 0.05% SDS (16). A serum pool of healthy male volunteers was used for calibration and assigned 1000 U/liter. The assay working range was 500-5000 U/liter, and the intra- and interassay coefficients of variation were less than 9%. Serum GHBP levels were measured by a modification of the ligand IFA (17) using an in-house monoclonal anti-GHBP antibody (18). Within-assay coefficient of variation was 9.4% at 115 pmol/liter and 6.1% at 1550 pmol/liter. At the same concentrations, between-assay coefficients of variation were 8.5 and 10.9%, respectively. The lower LOQ was 19 pmol/liter, and the linear range was 19–3500 pmol/liter.

Calculated pharmacokinetics parameters for GH included the observed maximal serum concentration (Cmax), the sample time at which Cmax was observed (Tmax), the half-life by linear regression (T1/2), and area under the concentration vs. time curve (AUC). AUC was calculated, using the trapezoidal rule, until the value was below the LOQ and was assessed as actual value and normalized to dose. For IGF-I, the parameters Cmax, Tmax, AUC, and dose-normalized AUC were similarly evaluated. IGF-I concentrations were also converted to SD scores by reference to a healthy population to standardize for age and gender (19).

Statistical analyses

The statistical analysis was essentially exploratory and not planned to assess bioequivalence. However, Cmax and AUC data for both GH and IGF-I were evaluated using a bioequivalence approach; data were log transformed and geometric mean ratios subjected to an ANOVA to compare daily GH with LB03002 first dose and LB03002 first dose with last dose. Differences in Tmax were evaluated using Wilcoxon signed-rank tests. For all samples where the GH concentration was more than 1 µg/liter, the IFA/ICMA ratio was compared between daily GH and first LB03002 and fifth LB03002 dose using a Kruskal-Wallis test.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Pharmacokinetics profile of GH

Serum GH concentrations after administration of daily GH and the first and fifth doses of LB03002 are shown in Fig. 1Go. In each case, the GH concentration before dosing was below the LOQ. After administration of the daily GH formulation, serum GH concentration rose rapidly to a peak and then declined to below the LOQ within 24 h. After dosing with LB03002, serum GH concentrations showed an extended peak at 6–15 h after the dose. The GH concentration remained elevated through 24 h and then declined; levels above the LOQ were seen in some patients at 72 h after dosing.


Figure 1
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  		FIG. 1. Serum GH levels after administration of daily GH ({square}) and the first ({circ}) and fifth (•) weekly doses of LB03002; GH values are plotted on a log scale as mean + SD.

 
The pharmacokinetics parameters for GH are summarized in Table 1Go. After the first dose of LB03002, Tmax was associated with a median of 7.5–15 h; this compared with a median Tmax of 3.5 h with the daily GH, which was significantly lower than the Tmax after LB03002 (P = 0.004). Cmax with LB03002 was approximately 2-fold higher than with the daily GH administration, despite the dose being about seven to eight times higher and consistent with the sustained release. In contrast, the GH AUC was 7- to 8-fold higher with LB03002, and thus the dose-normalized AUC (AUC/dose) did not show any significant difference between first-dose LB03002 and daily GH (P = 0.233) or between the first and fifth LB03002 doses (P = 0.142).


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  		TABLE 1. Serum GH pharmacokinetics parameters after the first and fifth weekly doses of sustained-release GH (LB03002) or administration of daily GH

 
The mean ratio for IFA and ICMA assessments of GH was 0.75 ± 0.15 with the daily GH formulation; the IFA/ICMA ratios with LB03002 were 0.63 ± 0.11 and 0.65 ± 0.10 after the first and fifth LB03002 doses, respectively. There was no significant difference between the formulations (P = 0.089), indicating comparable bioactivity. Furthermore, no trends toward difference in the IFA/ICMA ratios were detected between daily GH and LB03002 over the GH concentration ranges (Fig. 2Go).


Figure 2
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  		FIG. 2. IFA/ICMA ratio after administration of daily GH (black bars) and the first (white bars) and fifth (shaded bars) weekly doses of LB03002; bars show the 25–75th percentiles, and the vertical lines extend from the box as far as the data extend to a distance of 1.5 interquartile range at most, with values more extreme than this marked as plot symbols.

 
Pharmacodynamics changes

Mean serum IGF-I concentration was 150 ± 65 µg/liter during the daily GH treatment period before administration of the last daily GH dose. IGF-I concentrations were converted to SD scores, and the changes after daily GH and the first and fifth doses of LB03002 are plotted in Fig. 3Go. The IGF-I profile after LB03002 dosing was consistent with the sustained release of GH and showed a prolonged elevation, with the SD score above 0 for approximately 5 d. The IGF-I SD score returned to baseline before the next dose, indicating no progressive accumulation of IGF-I at the dose studied.


Figure 3
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  		FIG. 3. Mean serum IGF-I SD scores after administration of daily GH and the first and fifth weekly doses of LB03002.

 
The pharmacodynamics parameters summarized in Table 2Go indicate that IGF-I reached a peak level at a median of 15 h after the daily GH formulation, whereas the median Tmax after LB03002 was significantly (P = 0.004) greater at 48 h. Mean IGF-I Cmax with LB03002 was 34–41% higher than with the daily GH, whereas the AUC for IGF-I was approximately 7-fold greater with LB03002 than with the daily GH. Similar to the GH metrics, AUC adjusted for the GH dose was comparable between the preparations; AUC/GH dose with the first administration of LB03002 was slightly lower than with the daily GH (P = 0.048) but was not different after the fifth dose.


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  		TABLE 2. Pharmacodynamics parameters for serum IGF-I after the first and fifth weekly doses of LB03002 or daily GH

 
Serum concentrations of IGFBP-3 did not change greatly within the 24 h after daily GH administration (Table 3Go). During the washout period with no GH, the mean concentration fell slightly and was then increased within 24 h of the first LB03002 dose. Changes in ALS were similar to IGFBP-3, but more pronounced, with a decrease during the washout and increase within 24 h of the first LB03002 dose. GHBP tended to increase during the washout, but overall, the mean concentration was comparable with daily GH and LB03002 (Table 3Go).


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  		TABLE 3. Changes in IGFBP-3, ALS, and GHBP at the start and 24 h after daily GH and the first and fifth weekly doses of LB03002

 
Safety

Eight patients reported 14 adverse events during the last daily GH administration and washout period, and seven patients reported 21 events during LB03002 administration. One patient had a transient event of severe pain in a limb that resolved within 36 h without medication; all other events were mild to moderate in intensity. The most frequent adverse events were headache (four and seven events during daily GH/washout and LB03002, respectively) and weakness (five and two, respectively). Relationship to study medication was unlikely for all events during daily GH/washout and possible for 18 events during LB03002 administration. Injection site reactions were reported for five patients and were generally mild and transient, except for one erythema with diameter of redness more than 20 mm. All injection site reactions were resolved within 1–4 d without intervention.

Fasting serum glucose levels during daily GH therapy and subsequent LB03002 administration are shown in Fig. 4Go. There was no significant change after LB03002 administration compared with daily GH or the baseline after the washout period. No clinically relevant abnormal laboratory parameters were observed, and there was no evidence of antibodies to GH in any patient.


Figure 4
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  		FIG. 4. Fasting serum glucose concentrations in patients with AGHD treated with daily GH and LB03002. Daily GH was discontinued for 28 d (washout period) before five weekly injections of LB03002. Values represent mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The new preparation examined in the present study comprises recombinant human GH in hyaluronate microspheres (13). The pharmacokinetics profile in GH-deficient adults demonstrated that LB03002 resulted in sustained release of GH over several days from this hyaluronate-based formulation. Hyaluronate is a natural biomaterial found in connective tissues including skin and cartilage and, therefore, is degraded by hyaluronidase as part of the physiological process.

Serum GH concentration after LB03002 injection increased rapidly and was then maintained at a physiological level over several days but returned below the LOQ before each weekly injection, indicating that there was no progressive accumulation. Although the dose in the sustained-release formulation was seven to eight times that of the daily GH formulation, the Cmax with LB03002 was only approximately doubled. However, the extended period of increased GH concentration resulted in an AUC that was proportional to the dose, such that AUC normalized for dose was not different between daily GH and LB03002 formulations.

Because compliance of patients with daily injections might be limited during lifelong therapy, other attempts have been made to reduce the frequency of injections. For example, stably normal IGF-I concentrations have been demonstrated in adult GH patients treated with their normal daily dose but injected thrice a week (20).

Other sustained-release preparations for use with GH have been suggested, such as polyethylene glycol hydrogels (21) and polylactide coglycolide (12, 22, 23, 24). In a formulation designed to be given by monthly injection, sustained GH concentrations were achieved for 10–15 d but showed very high release initially after injection, with more than half of the GH released during the first 2 d (12, 22, 23). However, this formulation was recently withdrawn from the U.S. market because of manufacturing resource issues. With a recently reported formulation (hGH-Biosphere), there was an initial GH peak at 7.7 h and then a decrease to baseline, and a second peak occurred at 7 d (24). Although the preparation was concluded to be well tolerated and achieved IGF-I target levels, only the single-dose clinical study has been reported to date, with no comparison against daily GH because the patients were GH treatment naive.

Although the present study was not designed to formally assess bioequivalence, there was no difference in dose-normalized AUC between the daily GH and weekly LB03002, suggesting equivalence of the formulations with daily GH. This relative bioavailability is much higher than those reported with other formulations. Furthermore, the comparable ratios between the conventional GH assay and the immunofunctional GH assay indicated that comparable proportions of GH molecules from daily and weekly GH preparations circulate in an intact, bioactive form. Furthermore, in comparison with other sustained-release GH preparations described previously (12, 22, 23), LB03002 bears the advantage that smaller needles can be used for injection, together with a smaller injection volume.

IGF-I was maintained at target levels for approximately 3–5 d after LB03002 administration. The baseline before the first dose, after 4 wk with no GH treatment, was lower than the baseline before the fifth dose; however, there was a decrease to a trough level before the fifth dose of LB03002, indicating that there was no progressive accumulation of IGF-I. There also appeared to be effective increases in ALS and IGFBP-3, with both maintained at higher levels before the fifth dose than before the first dose of LB03002.

The safety results indicated that LB03002 was safe and well tolerated. The adverse events reported and the local reactions were comparable with what is already known from previous studies of daily GH. The laboratory evaluations, vital signs, and assessment of antibodies also indicated no consistent changes that might be drug related. Fasting serum glucose levels did not change significantly during LB03002 administrations. Despite some mild and transient injection site reactions, all of the patients in the present study said that they would prefer the sustained release preparation rather than the daily GH because of the greater convenience.

Effective GH pharmacokinetics and pharmacodynamics profiles were, therefore, shown in GH-deficient adults treated with multiple-dose LB03002 in this study. Clinical trials to establish whether long-term, weekly treatment with LB03002 can maintain the benefits of continued GH treatment in GH-deficient patients are being carried out. The present results indicate that this novel formulation is a suitable candidate for these long-term studies.


   Acknowledgments
 
We thank Drs. J. Maldonado and J. Klinger, Harrison Clinical Research, for their assistance in carrying out the study, and Dr. P. C. Bates, Cambridge Medical Writing Services, UK, for assistance in preparation of the manuscript.


   Footnotes
 
LG Life Sciences, Ltd., and BioPartners GmbH provided financial support for this study.

Disclosure statement: M.B. and N.E. have nothing to declare. J.K. and M.J.K. were previously employed by LG Life Sciences. C.S. was previously employed by and has equity interests in BioPartners GmbH. S.d.l.M. was previously employed by Harrison Clinical Research. C.J.S. consults for and received lecture fees from BioPartners GmbH.

First Published Online May 23, 2006

Abbreviations: AGHD, Adult GH deficiency; ALS, acid-labile subunit; AUC, area under the concentration vs. time curve; Cmax, maximal serum concentration; GHBP, GH-binding protein; ICMA, immunochemiluminometric assay; IFA, immunofunctional assay; IGFBP, IGF-binding protein; LOQ, limit of quantification; T1/2, half-life by linear regression; Tmax, sample time at which Cmax was observed.

Received March 7, 2006.

Accepted May 16, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals