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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2160
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1814-1820
Copyright © 2007 by The Endocrine Society

Pharmacokinetics and Pharmacodynamic Effects of an Oral Ghrelin Agonist in Healthy Subjects

Franziska Piccoli, Lukas Degen, Carol MacLean, Shajan Peter, Luisa Baselgia, Finn Larsen, Christoph Beglinger and Jürgen Drewe

Clinical Research Center, Department of Research (F.P., L.D., L.B., C.B., J.D.), Division of Gastroenterology (F.P., L.D., S.P., C.B.), and Department of Clinical Pharmacology and Toxicology (J.D.), University Hospital, 4031 Basel, Switzerland; and Ardana Bioscience Ltd. (C.M., F.L.), Edinburgh EH3 7HA, United Kingdom

Address all correspondence and requests for reprints to: Christoph Beglinger, M.D., Department of Gastroenterology, University Hospital, CH-4031 Basel, Switzerland. E-mail: beglinger{at}tmr.ch.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: An oral formulation of EP01572, a peptidomimetic growth hormone secretagogue, was studied. An oral delivery system would be preferable in many of the possible therapeutic indications of ghrelin agonists such as EP01572.

Objectives: Our objective was to establish the pharmacological profile and the GH-releasing activity of increasing oral doses of EP01572 in healthy volunteers. In addition, the pharmacokinetics and pharmacological effects of EP01572 were investigated after intraduodenal (ID) administration.

Setting: This study was a single-center escalating dose study with oral and ID applications.

Subjects and Methods: In the first part, EP01572 was given orally to 36 male subjects; the treatment consisted of one oral dose of either EP01572 or placebo (0.005, 0.05, and 0.5 mg/kg body weight). Six subjects received two additional oral doses of EP01572: 0.125 and 0.25 mg/kg body weight. In the second part, the following treatments were performed in a randomized order: 1) administration of a bolus of saline (placebo) to the small intestine; 2) ID administration of a bolus of EP01572 at 0.2 mg/kg body weight; 3) ID perfusion of a bolus of EP01572 at 0.35 mg/kg body weight; and 4) ID perfusion of a bolus of EP01572 at 0.5 mg/kg body weight.

Results: The oral and ID administration of EP01572 induced a rapid and dose-dependent increase in plasma drug concentrations and a potent GH release in healthy male volunteers.

Conclusions: This study showed that EP01572 was active with regard to stimulation of GH release in humans after oral and ID administration.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN IS A NOVEL 28-amino-acid peptide discovered in 1999. After the amino-acid sequence was ascertained, synthetic peptide could be produced. In their original characterization, Kojima et al. (1) showed that ghrelin was present in large amounts in the stomach. When injected iv, ghrelin induces GH release. Ghrelin-producing endocrine cells in the human digestive tract are most abundant in the oxyntic glands (predominantly found in the fundus) (2). Removal of the acid-producing part of the stomach decreased circulating ghrelin by 80%, in keeping with the oxyntic mucosa being the major source of circulating ghrelin (3).

Human studies with iv ghrelin have shown a dose-dependent stimulation of GH release (4, 5, 6). There were no significant adverse effects with iv doses of up to 500 µg (5). Apart from the marked increase in GH secretion elicited by ghrelin, there are effects on corticotroph and lactotroph secretions; furthermore, ghrelin may play a role in glucose homeostasis and insulin secretion (4, 5, 6, 7). Based on animal work and preliminary human studies, ghrelin has several potential clinical applications. Beneficial effects on hemodynamics (8, 9), stimulation of gastrointestinal motility, and stimulation of appetite are areas of potential application. Also, ghrelin potently enhanced appetite in healthy volunteers and increased energy intake in patients with cancer with impaired appetite (10, 11). Finally, ghrelin enhanced gastric emptying in rats and patients with diabetes with gastroparesis, suggesting that analogs of ghrelin may represent a new class of prokinetic agents (12, 13).

In recent years, GH-releasing peptides, especially peptidomimetics, have received considerable attention as potential drugs. EP01572 is an oral synthetic GH secretagogue (GHS) (14). It is a pseudotripeptide [chemical structure: H-Aib-(D)-Trp-(D)-gTrp-formyl] with increased stability and oral biovailability in dog studies (14); based on the chemical structure, EP01572 should have a better oral bioavailability than the GHS analog hexarelin. The hexapeptide hexarelin is well characterized as a reference GHS, but its clinical use is limited by its low systemic bioavailability and short half-life of elimination. EP01572 exhibits binding characteristics at the cloned human GHS receptor similar to ghrelin; ghrelin and EP01572 were able to elicit in vitro and in vivo stimulation of GH, suggesting that the compound acts as a ghrelin agonist, at least at the GHS receptor (14). Preliminary data with EP01572 in two normal young men showed that a single iv dose (1.0 µg/kg body weight) induced a strong and selective increase in GH levels; in an open, dose-escalating study with oral EP01572, an increase in GH secretion was seen at a dose of 0.06 mg/kg body weight. Safety investigations included recording of adverse events, physical examinations, electrocardiogram, vital signs, and extensive biochemistry and hematology laboratory measurements (14). Thus, EP01572 is a peptidomimetic GHS with potent GH-releasing activity. A detailed dose-finding and pharmacokinetic investigation has not been performed yet.

The aim of this study was therefore to evaluate the pharmacological profile and the GH-releasing activity of increasing single oral doses of EP01572 in healthy volunteers. Also tested was whether intraduodenal (ID) administration of the peptide improved systemic bioavailability.


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

A cohort of 36 healthy male subjects aged 23.6 ± 0.5 yr participated in the study. The weight of all subjects was within normal range considering their age, sex, and height (mean body mass index, 22.6 ± 0.4 kg/m2; range, 19.7–24.8 kg/m2).

Each subject gave written informed consent for the study. The protocols were approved by the State Ethical Committee of Basel. Before acceptance, each participant was required to complete a medical interview, receive a full physical examination, and participate in an initial laboratory screening. No one was taking any medication or had a history of food allergies or dietary restrictions.

Study design

The study was conducted as a randomized, placebo-controlled, dose-escalating study. Two treatments, separated by at least 7 d, were performed in 36 male subjects; one treatment consisted of one oral dose of either EP01572 or placebo, the second of a GHRH stimulation test. The treatments were identical in design except for the oral dose of EP01572. The subjects were divided into groups of 12 volunteers; in each group, nine subjects received one oral dose of EP01572 and three subjects received placebo. The following doses of EP01572 were tested: 0.005, 0.05, and 0.5 mg/kg body weight. Six subjects received two additional oral doses of EP01572: 0.125 and 0.25 mg/kg body weight. Blood was drawn at regular intervals in EDTA tubes containing aprotinin (500 kIU/ml blood) for hormone determinations: –30, –15, 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, and 300 min.

ID EP01572 administration

Four additional treatments, separated by at least 7 d, were performed in six subjects. The following treatments were performed in a randomized order: 1) administration of a bolus of saline (placebo) to the small intestine; 2) ID administration of a bolus of EP01572 at 0.2 mg/kg body weight; 3) ID perfusion of a bolus of EP01572 at 0.35 mg/kg body weight; and 4) ID perfusion of a bolus of EP01572 at 0.5 mg/kg body weight. The GHRH stimulation test was not repeated in these six subjects.

On the day before each experiment, subjects swallowed a radio-opaque polyvinyl feeding tube (external diameter: 8 French), which had an opening at the tip of the tube. The tube was inserted through the nose, because this procedure allowed the tube to be retained overnight and for the duration of the experiment. The tube was allowed to be transported to the duodenum overnight. In the morning, the position of the tube was located fluoroscopically and the tip of the tube was positioned 100 cm distally to the teeth. It was firmly attached to the skin behind the ear to prevent further progression of the tube during the experiment.

Blood was drawn at regular intervals as described previously.

GHRH stimulation test

The GHRH stimulation test was performed after fasting overnight. Blood samples for evaluation of GH levels were drawn at –30 min and just before injection of GHRH (time, –1 min) and 30, 60, 90, 120, 180, and 240 min after injection of GHRH (Ferring Pharmaceuticals, Wallisellen, Switzerland); GHRH was administered as a bolus iv injection at a dose of 1 µg/kg body weight. Samples were drawn by an indwelling catheter inserted into a forearm vein at least 0.5 h before the start of the sampling period. Subjects remained in a recumbent position from 1.5 h before injection of GHRH until the last blood sample was drawn.

Safety measurements

Safety investigations included recording of adverse events, physical examinations, electrocardiogram, vital signs, and extensive biochemistry and hematology laboratory measurements.

Hormones

The following hormones were measured: GH, prolactin, ACTH, cortisol, ghrelin, and insulin; in addition, glucose concentrations were measured with a hexokinase method.

Human GH (hGH) was measured with a specific RIA. The antibody is highly specific for hGH and does not crossreact with FSH, LH, prolactin, or TSH. The sensitivity of the assay was 0.01 ng/ml. At 17 ng/ml, the intraassay coefficient of variation (CV) was 4.6%, whereas the interassay CV was 6.6%.

ACTH was measured using an antibody that is highly specific for ACTH (no crossreactivity with {alpha}-MSH). The sensitivity of the assay was 5 pg/ml. At 40 pg/ml, the intraassay CV was 6.8%, whereas the interassay CV was 8.2%.

Cortisol was measured with a specific antibody; crossreactivity to aldosterone was less than 0.01%, whereas estriol, estrone, and androstenedione did not exhibit any detectable crossreactivity. The sensitivity of the assay was 20 µg/dl. At 30 µg/dl, the intraassay CV was 7.4%, whereas the interassay CV was 9.4%.

Prolactin was measured using an electrochemiluminescence assay (Roche, Basel, Switzerland). The assay is specific for prolactin and does not crossreact with hGH, human chorionic gonadotropin, FSH, LH, prolactin, or TSH. The assay sensitivity was 0.5 ng/ml. At 15 ng/ml, the intraassay CV was 1.8%, whereas the interassay CV was 2.8%.

Ghrelin was measured with a commercially available kit (Linco Research Inc., St. Charles, MO). The lowest level of ghrelin that can be detected by this assay is 93 pg/ml when using a 100-µl sample size. At 1 ng/ml, the intraassay CV was 10.0%, whereas the interassay CV was 14.7%. Insulin was measured with a commercial RIA.

EP01572 analysis

EP01572 plasma concentrations were determined using a liquid chromatography-tandem mass spectrometry method. At first, 500-µl human plasma samples were spiked with 10 µl EP01572 standard solution. The resulting internal standard concentrations were 400 ng/ml. After addition of 2 ml extraction solution (ethyl acetate and isopropanol), the test samples were vortexed for approximately 3 min and subsequently centrifuged at 2500 x g for 5 min at room temperature. The samples were then frozen at –20 C and, 30 min later, the organic phases were separated by decanting of the supernatants into new polypropylene tubes. After addition of 1 ml n-hexane and 200 µl acetic acid (0.1 M) to the organic phases, 250 µl from the resulting lower phases were removed and transferred into HPLC vials. From each test sample, a volume of 100 µl was injected into the HPLC system. The detection limit of the assay system was 0.2 ng/ml.

Material

The peptide was obtained from Europeptides, a member of Ardana Bioscience Ltd. (Edinburgh, UK).

Pharmacokinetic analysis

The following pharmacokinetic parameters were determined. The maximum plasma concentration (Cmax) and the time of its occurrence (Tmax) were determined by inspection of raw data. The apparent terminal half-life (T1/2), clearance over the fraction absorbed (Cl/F), the volume of distribution of the central compartment (Vc/F), and the area under the plasma concentration/time curve from time zero and extrapolated to infinity [AUC(0-{infty})] were estimated by noncompartmental analysis using the WinNonlin software (version 5.01; Pharsight Corp., Cary, NC).

Statistical analysis

No previous human pharmacokinetic data were available for this drug. The sample size was therefore based on practical considerations. Descriptive statistics were used for demographic variables such as age, weight, height, and body mass index. All subjects were included in the pharmacokinetic data analysis. Dose proportionality of EP01572 area under the curve (AUC) and Cmax was assessed by linear regression analysis. Pharmacokinetic parameters were compared by ANOVA. In case this analysis revealed significant differences, pairwise comparisons were performed using Tukey’s multicomparison test. All statistical analysis was done using SPSS for Windows software (version 14.0; SPSS Inc., Chicago, IL). Level of significance was P < 0.05. A similar procedure was used to analyze the results of EP01572-induced changes in plasma hormone concentrations using AUC analysis. Data are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Pharmacokinetics

Oral drug application. The lowest dose of EP01572 (0.005 mg/kg body weight) did not produce a relevant pharmacokinetic profile (data not shown). Higher oral doses of EP01572 induced a dose-dependent increase in plasma drug concentrations (Fig. 1Go). Plasma drug concentrations after oral administration peaked between 50 and 75 min (Fig. 1Go and Table 1Go), with the shortest time observed after the highest dose of EP01572. Dose proportionality was shown by linear regression analysis; a significant linear correlation was seen for both AUC (P < 0.004; R = 0.992) and Cmax (P < 0.002; R = 0.999) with dose.


Figure 1
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  		FIG. 1. Plasma concentrations of EP01572 after oral administration of different doses of EP01572. Data represent means ± SEM.

 

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  		TABLE 1. Single-dose pharmacokinetics of increasing oral doses of EP01572 in healthy male subjects

 
ID drug application. Plasma concentration of EP01572 peaked between 27.5 and 50 min (Table 2Go). A dose-dependent increase in plasma concentrations was seen in response to increasing doses of EP01572 (Fig. 2Go and Table 2Go). The peak concentrations and the AUCs were markedly higher after ID application in comparison to oral dosing (Table 2Go). Liner regression analysis revealed a dose proportionality for AUC and dose (P < 0.004; R = 0.992) and between Cmax and dose (P < 0.002; R = 0.999).


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  		TABLE 2. Single-dose pharmacokinetics of increasing ID doses of EP01572 in healthy male subjects

 

Figure 2
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  		FIG. 2. Plasma concentrations of EP01572 after ID administration of different doses of EP01572. Data represent means ± SEM.

 
GH-releasing activity

Orally and intraduodenally administered EP01572 stimulated hGH release in a dose-dependent manner (Figs. 3Go and 4Go). hGH release peaked at approximately 60 min after oral drug application, which is in good agreement with the time of maximal drug concentration (Tmax). The peak hGH response after intravenous GHRH administration was smaller than the hGH response after oral or ID EP01572 (Tables 3Go and 4Go). The elevation of hGH levels lasted for approximately 120 min after oral or ID EP01572 administration.


Figure 3
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  		FIG. 3. Stimulation of GH secretion over baseline. Effect of different oral doses of EP01572. Data represent means ± SEM.

 

Figure 4
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  		FIG. 4. Stimulation of GH secretion over baseline. Effect of different doses of oral EP01572. Effect of different ID doses of EP01572. Data represent means ± SEM.

 

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  		TABLE 3. GH secretion above baseline1

 

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  		TABLE 4. GH secretion above baseline1

 
Other hormonal responses to EP01572

The following hormonal responses were statistically compared for potential differences using ANOVA on AUCs and maximal concentrations of the respective hormone. At higher doses, EP01572 marginally increased circulating levels of prolactin, with the biggest response seen at the highest dose (Fig. 5CGo), but ACTH and cortisol levels were not significantly changed (Fig. 5Go, A and B). EP01572 did not significantly alter plasma concentrations of glucose and insulin (Fig. 6Go) or ghrelin levels (data not shown). All these hormonal parameters remained unchanged during placebo administration.


Figure 5
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  		FIG. 5. A, Effect of different doses of oral EP01572 on ACTH secretion over baseline. Data represent means ± SEM. B, Effect of different doses of oral EP01572 on cortisol secretion over baseline. Data represent means ± SEM. C, Effect of different doses of oral EP01572 on prolactin secretion over baseline. Data represent means ± SEM.

 

Figure 6
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  		FIG. 6. A, Plasma glucose concentrations in response to different doses of oral EP01572. Data represent means ± SEM. B, Insulin concentrations in response to different doses of oral EP01572. Data represent means ± SEM.

 
Safety assessments of EP01572

All study subjects tolerated EP01572 well, and no adverse events were recorded. Blood pressure and heart rate were not affected by increasing doses of oral or ID EP01572 (Table 5Go). Adverse events were not observed by the attending physician or reported by the volunteers.


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  		TABLE 5. Cardiovascular parameters in response to increasing oral doses of EP01572 in healthy male subjects

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study examined the pharmacokinetics and hormonal effects of oral and ID EP01572, a synthetic ghrelin agonist. The results reveal that 1) oral and ID administration of EP01572 induced a rapid and dose-dependent increase in plasma drug concentrations and 2) a potent GH release in healthy male volunteers.

The pharmacokinetics of EP01572 determined in healthy young males after oral or ID applications reveal several important aspects. The drug is readily absorbed from the gastrointestinal tract, with peak concentrations achieved on average within 50 min after ID application and within 75 min after oral dosing. Elimination (half-life) of EP01572 ranged from 73 to 114 min after different doses of oral or ID application. Intravenous dosing of EP01572 was not performed in this study; therefore, the absolute bioavailability cannot be calculated from the data obtained in the present study. The mean peak concentrations in plasma after the highest dose of EP01572 (0.5 mg/kg body weight) were 20–30% higher after ID dosing compared with an identical oral dose. This finding would suggest that a small amount of drug is degraded during the passage through the stomach. Alternatively, the higher bioavailability after ID administration may reflect an effect of higher local concentrations at the absorption site. These higher concentrations could result in a higher gradient for passive diffusion and may saturate possible efflux mechanisms (such as P-glycoprotein) or metabolic enzymes in the enterocytes of the duodenum, resulting in a higher fraction of the administered dose absorbed. However, these explanations are speculative rather than based on experimental evidence.

As discussed previously, EP01572 is a novel, synthetic ghrelin agonist, which is readily absorbed from the gastrointestinal tract. Ghrelin potently stimulates GH release. The GH-releasing effects of ghrelin are thought to be mediated by specific receptors, GHS-Rs, mainly present at the pituitary and hypothalamic level. Because EP01572 is a synthetic GHS, we assume that the drug exerts its action in the same way. The present results are compatible with this assumption: single oral or ID doses of EP01572 resulted in a dose-dependent elevation of circulating hGH; the increase in hGH depicted as AUC was significant for all doses greater than 0.125 mg/kg body weight.

Using ANOVA on AUCs and maximal concentrations, the compound did not significantly affect prolactin, ACTH, and cortisol concentrations. EP01572 exhibited minor stimulatory effects on prolactin secretion, but only at higher doses. At present, we cannot exclude that high concentrations of EP01572 may exert a stimulatory effect on these hormones because a limited number of subjects was investigated here. The results are consistent with the effects of ghrelin or the effects of the ghrelin agonist hexarelin, a synthetic analog with poor bioavailability (15). Thus, the effects of EP01572 are most likely direct effects at the pituitary level and in the hypothalamus (16).

The pharmacodynamic properties of EP01572 on hGH release have potential clinical applications. It has been reported that synthetic GHSs have protective effects on ischemic cardiac muscle (17, 18, 19). Intravenous ghrelin has also been shown to stimulate gastric emptying of solids in healthy humans (20). Similar findings have been made in experimental animals (12, 21) and recently in patients with idiopathic and diabetic gastroparesis (13, 22, 23). Intravenous ghrelin has also been shown to stimulate appetite and food intake in healthy volunteers and in patients with tumors with impaired appetite (10, 11, 20, 24). An iv or sc application is, however, cumbersome and impractical for chronic treatment regimens; EP01572, with its pharmacokinetic profile, would seem to be a very promising compound that could overcome the problems associated with the iv administration. Whether EP01572 administration is beneficial in the different clinical applications remains to be shown. Protocols are being developed that will specifically address these questions.


   Acknowledgments
 
We thank the team of the Clinical Research Centre (Mrs. Claudia Bläsi and Mrs. Susanne Zehnder) and Sylvia Ketterer and Gerdien Gamboni for expert technical assistance. We also thank Prof. Peter Huber, Central Laboratory, University Hospital Basel, for measuring hormone concentrations.


   Footnotes
 
This work was supported by grants of Ardana Pharma, Edinburgh (UK), and the Swiss National Science Foundation (Grant 3200-065588.04/1).

Disclosure Summary: F.P., L.D., S.P., and L.B. have nothing to declare. C.B. and J.D. consult for Ardana Bioscience and have received grants from the company. C.M. and F.L. are employees of Ardana Bioscience and have equity interests in the company. C.B. received an unconditional research grant from Ardana Bioscience Ltd., Edinburgh, UK, for this study.

First Published Online February 6, 2007

Abbreviations: AUC, Area under the curve; Cmax, maximum plasma concentration; Cl/F, clearance over the fraction absorbed; CV, coefficient of variation; GHS, GH secretagogue; hGH, human GH; ID, intraduodenal; T1/2, terminal half-life; Tmax, time of maximal drug concentration; Vc/F, volume of distribution of the central compartment.

Received October 3, 2006.

Accepted January 31, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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C. M. MacLean, A.-T. Casanova, L. Baselgia-Jeker, N. Neave, F. Larsen, L. Skillern, J. Drewe, and C. Beglinger
Effect of Food on the Pharmacokinetics and Pharmacodynamics of an Oral Ghrelin Agonist (ARD-07) in Healthy Subjects
J. Clin. Pharmacol., May 1, 2009; 49(5): 553 - 559.
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