Download Oral Octreotide Absorption in Human Subjects: Comparable

ORIGINAL
E n d o c r i n e
ARTICLE
C a r e
Oral Octreotide Absorption in Human Subjects:
Comparable Pharmacokinetics to Parenteral
Octreotide and Effective Growth Hormone
Suppression
S. Tuvia, J. Atsmon, S. L. Teichman, S. Katz, P. Salama, D. Pelled, I. Landau,
I. Karmeli, M. Bidlingmaier, C. J. Strasburger, D. L. Kleinberg, S. Melmed,
and R. Mamluk
Chiasma (S.T., S.L.T., S.K., P.S., D.P., I.L., I.K., R.M.), Jerusalem 91450, Israel; Clinical Research Center
(J.A.), Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv
69978, Israel; Medizinische Klinik und Poliklinik IV (M.B.), Klinikum der Universität, 80336 Munich,
Germany; Division of Clinical Endocrinology (C.J.S.), Department of Medicine, Campus Mitte, Charité
Universitätsmedizin Berlin, 10117 Berlin, Germany; School of Medicine (D.L.K.), New York University,
New York, New York 10016; and Department of Medicine (S.M.), Cedars Sinai Medical Center, Los
Angeles, California 90048
Context: Oral administration of a novel octreotide formulation enabled its absorption to the
systemic circulation, exhibiting blood concentrations comparable to those observed with injected
octreotide and maintaining its biological activity.
Objectives: The aim of the study was to determine oral octreotide absorption and effects on
pituitary GH secretion compared to sc octreotide injection.
Design: Four single-dose studies were conducted in 75 healthy volunteers.
Intervention: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 ␮g octreotide
were administered.
Main Outcome Measure: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion.
Results: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted
in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma
decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc
octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration,
3.77 ⫾ 0.25 vs. 3.97 ⫾ 0.19 ng/ml; mean area under the curve, 16.2 ⫾ 1.25 vs. 12.1 ⫾ 0.45 h⫻ng/ml);
and median time ⱖ0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide
resulted in basal (P ⬍ 0.05) and GHRH-stimulated (P ⬍ 0.001) mean GH levels suppressed by 49 and
80%, respectively.
Conclusions: The results support an oral octreotide alternative to parenteral octreotide treatment
for patients with acromegaly. (J Clin Endocrinol Metab 97: 2362–2369, 2012)
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1179 Received January 23, 2012. Accepted April 2, 2012.
First Published Online April 26, 2012
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Abbreviations: AE, Adverse event; AUC, area under the curve; Cavg, average GH concentration; Cmax, peak plasma concentration; PD, pharmacodynamic; PK, pharmacokinetic;
PPI, proton-pump inhibitor; Tmax, time to Cmax.
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J Clin Endocrinol Metab, July 2012, 97(7):2362–2369
ctreotide, a synthetic octapeptide analog of human
somatostatin (1–3), is used for treatment of acromegaly and neuroendocrine tumors. Octreotide is more
active than native somatostatin in inhibiting GH, insulin,
glucagon, and other hormones in animals and in man (1,
2). The difference is due to an elimination half-life of 2–3
min for somatostatin in humans, compared with approximately 100 min for octreotide (4). Octreotide administration also decreases splanchnic blood flow (5, 6) and
inhibits release of serotonin, gastrin, vasoactive intestinal
peptide, secretin, motilin, and pancreatic polypeptide (7).
Clinically, octreotide use has been limited to the parenteral
route because it exhibits low and variable systemic bioavailability upon oral administration (8 –10). In chronic
conditions, such as acromegaly, the burden of injectable
drug regimens adversely impacts patients’ quality of life
(11, 12). There have been a number of attempts to augment octreotide intestinal absorption to enable oral octreotide treatment (9, 13–16), but none have become commercially available.
Most recently, a new formulation was reported (17),
combining octreotide and other excipients to form an oily
suspension of hydrophilic particles in a lipophilic medium
allowing enhanced intestinal permeability. This preparation was shown in rats to facilitate a transient paracellular
passage of octreotide across the gastrointestinal wall in the
small intestines (18). Rat enteral octreotide absorption
was shown to be dose-dependent, and the effects on the
GH levels were comparable to the injectable form of octreotide (17). The present set of studies was designed to
test this new formulation in humans and compare pharmacokinetics (PK) of a single-dose of oral and injectable
O
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(sc) octreotide in healthy volunteers, to assess the safety
and tolerability of the new oral octreotide formulation,
and to test whether orally absorbed octreotide is functional and exerts pharmacological suppression of pituitary GH release.
Subjects and Methods
Subjects
Seventy-five healthy volunteers were recruited in the Tel Aviv
Sourasky Medical Center (Tel Aviv, Israel; n ⫽ 51) and in Celerion, Inc. (Lincoln, NE; n ⫽ 24) and screened for clinically significant conditions. Four separate studies were carried out at the
two sites (Fig. 1). Criteria for inclusion in studies 1, 2, and 4
included subjects between 18 and 49 yr of age, body mass index
of 19 to 30 kg/m2, and weight of at least 55 kg. In study 3, the
criteria were age between 18 and 35 yr and body mass index of
19 to 25 kg/m2. Volunteers were excluded if they tested positive
for drugs in a urine test, smoked (in last 6 months), were treated
with another investigational drug within 3 months before screening, or consumed excess alcohol and/or prescription or over-thecounter medications, including vitamins, herbal and/or other dietary supplements 14 d before the study.
All participants gave written informed consent according to
the Declaration of Helsinki, Seoul and Good Clinical Practice as
outlined by ICH guidelines. Experimental protocols were approved by the Institutional Review Board for the Tel Aviv
Sourasky Medical Center (no. 20090885, 20100253), and as
part of an IND protocol (IND 108,163) for Celerion, Inc.
Study treatments
Injectable octreotide (Sandostatin; Novartis, Basel, Switzerland) (19) was provided as sterile 1-ml ampoules, each containing 0.1 mg of octreotide acetate. The drug was injected sc in the
FIG. 1. Trials profile. Seventy-five healthy volunteers were enrolled in four crossover open-label trials in Tel Aviv, Israel (n ⫽ 3) and Lincoln,
Nebraska (n ⫽ 1). Of them, 71 volunteers underwent single 3-, 10-, and 20-mg (or 10-mg twice) oral administration or a single sc injection of 0.1
mg of octreotide acetate.
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deltoid area. Oral formulation (Octreolin; Chiasma, Jerusalem,
Israel) consisted of 3, 10, or 20 mg unmodified octreotide acetate, in an oily suspension including polyvinyl pyrrolidone, sodium caprylate, polysorbate 80, glyceryl monocaprylate, glyceryl tricaprylate, and magnesium chloride (20). The oral
preparations were administrated in enteric-coated gelatin capsules after a 10-h fast and were swallowed with 240 ml water. In
study 2, participants consumed a high-fat, high-calorie meal
(900 –1000 calories) immediately before the oral octreotide dosing. The composition of the tested meal was 55% energy derived
from fat, 29% energy from carbohydrates, and 16% energy from
protein. In study 4, a delayed-release esomeprazole capsule (40
mg Nexium; AstraZeneca Inc., Wilmington, DE) was additionally administered daily on d 2 through 7.
Study design
PK and pharmacodynamic (PD) data were collected to evaluate the oral octreotide formulation in healthy adult volunteers
in four separate studies (Fig. 1). In study 1, octreotide PK measurements were performed in 12 males (mean age, 23 yr) using
a partly randomized, dose-escalation two-way crossover design,
with 7-d washout intervals. Blood octreotide levels were measured after oral administration of 3, 10, and 20 mg octreotide or
injection sc of 0.1 mg octreotide. Next, the food effect was studied (study 2) in 24 volunteers (11 females and 13 males; mean
age, 29 yr) using a randomized, single-dose, two-period, crossover design. Oral octreotide capsule (20 mg) was administered to
24 participants while fasting 10 h before and during dosing, or
after 10-h fasting and consumption of a high-fat, high-calorie
meal 0.5 h before dosing. Parenteral octreotide (0.1 mg) was
subsequently administered sc. A PK/PD study (study 3) was conducted next in 24 volunteers (13 females and 11 males; mean age,
24 yr) to evaluate the PK results of a single 20 mg octreotide oral
dose and its effects on GH suppression. Additionally, the duration of intestinal permeability was evaluated after oral octreotide
capsule administration (data not shown in this report). The study
consisted of four dosing periods and three 2-wk washout periods
between doses. Five subjects discontinued before completing the
study. Lastly, the effect of proton-pump inhibitor (PPI), esomeprazole, on oral octreotide absorption was assessed in 14 volunteers (seven females and seven males; mean age, 29 yr; study
4). Subjects received 20 mg oral octreotide at first, followed by
6 d of PPI administration. On d 7, a second dose of oral octreotide
(20 mg) was coadministered with the PPI, and octreotide blood
levels and PK were compared between d 0 and 7. One subject
discontinued before completing the study.
Study assessment
Safety was evaluated at enrollment and after the indicated
treatments by measuring vital signs, physical examination, 12lead electrocardiogram, and clinical laboratory assessments including blood biochemical and hematological parameters and
urinalysis.
Before dosing and/or high-fat meal consumption, subjects
were required to fast for at least 10 h. An indwelling iv catheter
was placed in each subject for the purpose of repeated blood
sampling. A basal, i.e. pretreatment, blood sample was obtained,
and a single octreotide injection (0.1 mg) or capsule (3, 10, or 20
mg) was then administered sc or orally, respectively. Repeated
blood samples (1.0 ml each) were obtained at 5, 10, 20, 30, and
45 min and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h after the
J Clin Endocrinol Metab, July 2012, 97(7):2362–2369
end of the sc injection and at 20 and 40 min and then at 1, 1.33,
1.66, 2, 2.33, 2.66, 3, 3.33, 4, 5, 6, 8, 12, and 24 h after oral
dosing. Blood was collected into EDTA-containing tubes and
centrifuged at 1000 ⫻ g for 15 min at 4 C to isolate plasma.
Plasma samples were stored at ⫺80 C for later octreotide
measurements.
The effect of the oral octreotide treatment (20 mg) was tested
on the GH levels using the GHRH/arginine test (21, 22). GHRH
(Ferring Pharmaceuticals, Middlesex, UK) 1 ␮g/kg was administered as an iv bolus 2 h after oral octreotide dosing (“time
zero”), followed immediately by a 30-min infusion of L-arginine
(30 g; Phebra Pty Ltd., Lane Cove, Australia) in 300 ml saline.
Blood samples were drawn at 3, 2.66, 2.33, 2.0, 1.66, 1.33, 1.0,
0.66, and 0.33 h before infusion, with the infusion, and at 0.25,
0.5, 0.75, 1, 1.25, 1.5, 1.75, and 2 h after GHRH/arginine administration for serum GH and octreotide measurements.
Bioanalytical assessment
Octreotide plasma levels were obtained using HPLC with
column-switching guard column (ACQUITY UPLC BEH C18
VanGuard); precolumn (2.1 mm ⫻ 5 mm), 1.7 ␮m; and analytical column, (ACQUITY UPLC BEH C18, 2.1 mm ⫻ 100 mm,
1.7 ␮m) (all from Waters Corp., Milford, MA); and mass spectrometer (MS)/MS (Sciex API 4000, Triple quadrupole; AB
Sciex, Framingham, CT) detection using multiple reaction monitoring positive ion electrospray with Q1/Q3 mass transitions of
510/120 for the octreotide and 513/120 for the internal standard, [13C6Phe3]octreotide (cyclic). The isocratic elution used a
mix of 80% mobile phase A (0.1% formic acid in water) and
20% of mobile phase B (0.1% formic acid in acetonitrile) from
0.0 to 4.7 min. The limit of quantization for octreotide concentration in plasma was defined as 0.025 ng/ml. The interassay
coefficients of variation ranged from 3.15 to 5.71%, and intraassay coefficients of variation ranged from 0.01 to 14.6%.
Serum GH concentrations were determined using an immunochemiluminometric method (IDS Immunodiagnostic Systems,
Boldon, UK). This double monoclonal antibody-based sandwich
assay measures only 22-kDa GH, exhibiting no cross-reactivity
with other GH forms. The assay had a 0.05 ng/ml limit of detection, and linearity was established in the 0.05–100 ng/ml dynamic range (23).
Data analysis
Pharmacokinetics
Octreotide PK parameters [peak plasma concentration
(Cmax), time to Cmax (Tmax), elimination half-life, and AUC]
were calculated using standard noncompartmental methods
from the plasma concentration vs. time in each subject. PK calculations were performed using SAS version 9.1.3. (SAS Institute, Inc., Cary, NC). Cmax and Tmax were determined directly
from the measurement results, and AUC values were determined
using the linear trapezoidal rule and extrapolated to infinity using the last octreotide values measured above the detection limit.
Pharmacodynamics
Effects of octreotide on serum GH levels before and after
GHRH induction were assessed. Cmax of GH was derived directly from the data gathered after GHRH induction (2 to 4 h).
The GH AUC was calculated using the linear trapezoidal
method, and the average GH concentration (Cavg) was calcu-
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TABLE 1. Incidence of the most common side effects encountered after single oral or sc injection of octreotide
acetate to healthy subjects
Oral octreotide acetate
(n ⴝ 105)b
Frequency of side effectsa
Injection site reaction
Abdominal pain
Diarrhea
Headache
Nausea
Feces discolored
No. of events
0
16
8
10
7
11
Subcutaneous injection of
octreotide acetate (n ⴝ 26)
%
0
15
8
10
7
10
No. of events
10
3
2
2
2
1
a
Events listed constitute more than 5% of documented AE.
b
Seventy-five healthy subjects participated in four separate studies; 34 volunteers received oral octreotide acetate more than once.
lated as the arithmetic mean of the concentrations. Both parameters were calculated per treatment and over the indicated time
frame in the assay, i.e. at baseline (baseline to 1 h), before (baseline to 2 h), and after GHRH induction (2 to 4 h). The basal and
the GHRH-induced Cavg and AUC in the oral octreotide treated
and nontreated groups were compared using a two-sided paired
Student’s t test.
Results were expressed as mean ⫾ SE if normally distributed
or as median (range) if the data were skewed. A significance level
of P ⬍ 0.05 was used for all statistical analyses. A total of 71
subjects (all completed the studies) were included in the PK, PD,
and safety analysis sets (all exposed).
Results
Subjects
Seventy-five subjects who qualified for study were included in the four studies (Fig. 1). Of these, 71 underwent
20 mg oral octreotide dosing during the studies (95%);
four discontinued participation (5.3%) for non-drug-related reasons (three in study 1 and one in study 3). Of the
71 that dosed with 20 mg of oral octreotide, 65 volunteers
received oral octreotide more than once. All subjects tolerated both oral and sc treatments, and no serious adverse
events (AE) were documented. Incidences of the key AE
encountered are presented in Table 1. In total, 60 and 21
AE were recorded in 37 of 105 (35%) and 15 of 36 (42%)
healthy subjects after oral and parenteral administration
of octreotide, respectively. The most common AE were
injection site reaction (38%) and abdominal pain (15%) in
the injectable or oral octreotide groups, respectively.
In study 1, a few subjects reported light-colored stools
1 or 2 d after a single dose of Octreolin. Although this
occurred only after administration of the oral preparation,
it was not consistent among subjects and was transient.
There was no clinical or laboratory evidence of gallbladder dysfunction, nor did subjects report associated diarrhea or change in odor, which might indicate steatorrhea.
At the time the subjects made their reports, this AE had
already resolved, and therefore stools were not collected
%
38
12
8
8
8
4
for further analysis. We cannot explain this finding which,
incidentally, was not reported in other studies being performed simultaneously.
PK parameters
Octreotide plasma concentrations after 3, 10, and 20
mg oral octreotide administration are shown in Fig. 2.
Observed changes in plasma octreotide PK parameters
were proportional to the oral dose [mean ⫾ SE values of
Cmax, 0.5 ⫾ 0.1, 2.0 ⫾ 0.2, and 3.2 ⫾ 0.7 ng/ml, respectively; AUC0-t, 1.9 ⫾ 0.3, 6.5 ⫾ 0.8, and 14.8 ⫾ 4.3 h⫻ng/
ml, respectively; and AUC⬁, 2.0 ⫾ 0.3, 8.0 ⫾ 0.8, and
15.0 ⫾ 4.2 h⫻ng/ml, respectively]. Likewise, the PK parameters of a single dosing of 20 mg oral octreotide at two
capsules of 10 mg or a single capsule of 20 mg were comparable (data not shown). The PK profiles were also characterized by median lag time of 0.3 h (range, 0.3–1.7 h)
and comparable mean decay rates (1.9 ⫾ 0.1, 2.3 ⫾ 0.1,
FIG. 2. Dose-response effect of oral octreotide acetate on plasma
octreotide levels. Mean ⫾ SE of fasting plasma octreotide levels in
healthy volunteers after single 3-mg (closed diamonds; n ⫽ 12),
10-mg (closed squares; n ⫽ 12), and 20-mg (closed diamonds; n ⫽ 9)
oral administration of octreotide acetate.
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FIG. 3. Comparable plasma octreotide concentrations after oral or sc
injection of octreotide acetate. Mean plasma concentrations of
octreotide after a single oral administration of 20 mg octreotide
acetate (closed diamonds, n ⫽ 24; closed squares, n ⫽ 12; closed
circles, n ⫽ 17) and single sc injection of 0.1 mg octreotide acetate
(closed squares, dotted line; n ⫽ 14) to healthy volunteers.
and 2.5 ⫾ 0.2 h at 3-, 10-, and 20-mg doses, respectively).
Single octreotide capsules (20 mg) or injections (0.1 mg)
were also administered orally or sc, respectively, to 12–24
healthy volunteers in studies 2, 3, and 4. Profiles of plasma
octreotide levels vs. time are presented in Fig. 3, and Table
2 provides the mean PK parameters after oral and parenteral octreotide dosing. After sc injection, octreotide levels
increased rapidly, peaked at 0.6 h (Cmax, 3.97 ⫾ 0.19
ng/ml), and remained above 1.0 ng/ml for 3.9 h. After oral
capsule administration, plasma octreotide concentrations
increased more slowly than after injection, with a comparable peak at 2.7 h (Cmax, 3.77 ⫾ 0.25 ng/ml), and
sustained a mean 1.0 ng/ml or greater octreotide level for
5.9 h. Plasma octreotide concentrations declined in the
injectable and oral groups with a comparable mean halflife (2.25 ⫾ 0.05 and 2.38 ⫾ 0.07 h, respectively) to subtherapeutic levels (⬍0.5 ng/ml) after 6 and 8 h,
respectively.
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Octreotide uptake after an oral administration of 20
mg octreotide before and after food intake was investigated in study 2. Lower plasma octreotide levels were measured and calculated for all PK parameters (Cmax, 0.42 ⫾
0.12 and 4.1 ⫾ 0.46 ng/ml, respectively; AUC0-t, 1.4 ⫾ 0.2
and 16.8 ⫾ 2.0 h⫻ng/ml, respectively; and AUC⬁, 1.6 ⫾
0.2 and 17.0 ⫾ 1.6 h⫻ng/ml, respectively) in volunteers
who received a high-fat and high-calorie meal before an
oral octreotide intake, compared with the fasted group.
Consistently, reduced (90%) bioavailability was observed
in the fed group. In addition, pretreatment for 5 d with
esomeprazole had a more variable effect on oral octreotide
absorption (Cmax, 4.8 ⫾ 0.7 and 2.5 ⫾ 0.3 ng/ml, respectively; AUC0-t, 20.0 ⫾ 4.8 and 10.1 ⫾ 1.2 h⫻ng/ml,
respectively; and AUC⬁, 4.9 ⫾ 0.7 and 10.1 ⫾ 1.2 h⫻ng/
ml, respectively) with a mean approximately 40% decrease (range, ⫺85% to ⫹115%) in octreotide bioavailability, compared with the control group.
Effect of oral octreotide
Response of GH to GHRH-arginine stimulation with
or without oral octreotide treatment was evaluated in 16
healthy volunteers in study 3. Mean GH concentrations
measured before oral octreotide administration, as well as
GH levels before and after GHRH induction are shown in
Fig. 4. Normal pulsatile GH secretion in healthy adults is
known to be fairly low (24). Indeed, baseline GH blood
concentrations were variable, and overall levels were negligible (approximately 1–3 ng/ml). However, low basal
GH secretion before GHRH-arginine iv injection was significantly suppressed (P ⬍ 0.05) by oral octreotide treatment (Fig. 4B and Table 3). Peak GH elicited after GHRHarginine stimulation (⬃50 ng/ml) was strongly suppressed
(⬃10 ng/ml; Table 3) by prior oral octreotide dosing (20
mg). Similarly, strong inhibition (80%) was shown (P ⬍
0.001) for the AUC and Cavg parameters of serum GH in
this group (Table 3).
TABLE 2. Plasma octreotide levels after single oral administration or sc octreotide acetate injection to healthy
volunteers
Parametera
Cmax (ng/ml)
Tmax (h)
AUC0-t (h⫻ng/ml)
AUC⬁ (h⫻ng/ml)
Half-life (h)
Time lag (h)
Time ⱖ0.5 ng/ml (h)
Time ⱖ1 ng/ml (h)
Oral octreotide acetate (20 mg)
3.77 ⫾ 0.25 (71)
2.67 (71) 关0.330 – 6.04兴
16.2 ⫾ 1.25 (71)
19.0 ⫾ 1.4 (71)
2.38 ⫾ 0.07 (71)
0.33 (31) 关0.33–1.67兴
7.67 (70) 关0.67–23.7兴
6.00 (66) 关0.33–11.7兴
Subcutaneous injection of octreotide
acetate (0.1 mg)
3.97 ⫾ 0.19 (26)
0.64 (26) 关0.167– 4.00兴
12.1 ⫾ 0.45 (26)
12.4 ⫾ 0.47 (26)
2.25 ⫾ 0.05 (26)
b
5.88 (26) 关3.92–7.92兴
3.92 (26) 关2.67– 4.92兴
Values are expressed as arithmetic mean ⫾ SE (number), except for Tmax, Time lag, and Time ⱖ0.5 or 1 ng/ml, which are expressed as median
(number) 关range兴.
a
b
Not applicable to the sc route of administration.
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FIG. 4. Oral administration of octreotide acetate suppresses the basal
GH levels and secretory response to GHRH stimulation. A, Plasma GH
and octreotide (closed triangles) concentrations (mean ⫾ SE; n ⫽ 16)
before and after GHRH/arginine administration, with (closed squares)
and without (closed circles) oral octreotide acetate treatment (20 mg).
B, Inhibition of endogenous GH levels by oral octreotide acetate was
also noted within the first 2 h of dosing (arrow), before GHRH
stimulation.
Discussion
Systemic exposure of orally administrated octreotide after
(20 mg) was similar to that of sc injection (0.1 mg) of this
same peptide in healthy volunteers. Similarly, a comparable safety profile was shown for both octreotide formulations, except for injection-related discomfort in the sc
injections. Oral octreotide absorption from enteric-coated
capsules resulted in a dose-dependent increase in systemic
exposure. Finally, basal levels of GH and the GHRH-stim-
TABLE 3.
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ulation of GH secretion were significantly suppressed by
a single oral octreotide dose.
Both parenteral and oral octreotide formulations were
well tolerated by the participants. Octreotide has been
clinically used for the treatment of acromegaly for over
two decades (25). Commercially available octreotide
products include a refrigerated sterile octreotide solution
for sc daily injection and a 1-month sustained-release octreotide depot formulated in poly-lactic-co-glycolic acid
for im injection. These formulations have a well-established safety profile in which the drug-related AE include
mostly mild-to-moderate and transient injection-site reactions, gastrointestinal disturbances, and occasional hyperglycemia (26). Moreover, parenteral octreotide administration was associated with pain and discomfort during
daily/monthly injection. The oral preparation tested here
was shown to exhibit a comparable safety profile to injectable octreotide during a 3-month daily administration
in monkeys (17) and after single dosing in the present
study in healthy volunteers. In the current study, both
treatment groups exhibited 8 –15% incidences of gastrointestinal-related discomfort and headaches, and approximately 40% of volunteers who received the sc octreotide
injection reported irritation at the injection site, consistent
with previously reported AE of the injectable drug (12,
26). The oral octreotide formulation may therefore be
considered as an easy, nonpainful, and comparably safe
formulation compared with the parenteral drug.
PK exposure observed in this study with single 3, 10,
and 20 mg oral octreotide administrations were dose proportional, and the 20-mg dose was comparable to a
0.1-mg sc injection. The chronic requirement for octreotide treatment in acromegaly patients justifies the development of oral alternatives. Early reports (8, 10, 27)
suggested enteral absorption of octreotide in aqueous solution; however, the measured bioavailability was low
with a marked interindividual variability. Additional attempts to increase intestinal permeability of this octapeptide by employing bile acids in rats and humans (9), poly-
Inhibition of basal and GHRH-stimulated GH release by oral octreotide acetate
Oral octreotide acetate (20 mg)
ⴚ
a
Parameter
AUC (h⫻ng/ml)
Cavg (ng/ml)
a
b
Basal GH
2.4 ⫾ 0.7c
1.3 ⫾ 0.4
ⴙ
GHRH
64.1 ⫾ 6.6
56.1 ⫾ 6.0
Basal GH
0.8 ⫾ 0.3*
0.5 ⫾ 0.2*
% GH inhibition
GHRH
11.5 ⫾ 3.2**
12.2 ⫾ 3.6**
Basal GH
49 ⫾ 16
44 ⫾ 17.5
GHRH
80 ⫾ 4.5
80 ⫾ 4.8
Predosing GH levels of AUC (h⫻ng/ml) and Cavg (ng/ml) were 1.9 ⫾ 0.6 and 1.1 ⫾ 1.4, respectively.
b
Postdosing GH levels for up to 2 h, at which time the GHRH stimuli were induced (see text for further details).
c
Values are expressed as mean ⫾ SE (n ⫽ 16).
* P ⬍ 0.05; and ** P ⬍ 0.001 were obtained by two-tailed paired Student t test comparison between the oral octreotide treated and nontreated
groups.
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(alkyl cyanoacrylate) nanocapsules in estrogen-treated
rats (28), N-trimethyl chitosan chloride in rats and pigs
(15, 16), superporous hydrogel polymers in pigs (13), and
alkyl-saccharides in mice (29) reported encouraging results. Notwithstanding, to the best of our knowledge,
none of these formulations has been developed further. An
oily suspension formulation increased rat intestinal permeability and enabled octreotide enteral absorption (17).
In the current study, plasma octreotide levels increased
proportionally with the oral dose in terms of Cmax and
AUC. The oral encapsulated formulation resulted in peak
plasma octreotide 2 h later in comparison with approximately 0.6 h for the injectable drug; nevertheless, in the
clinical context of the sustained endocrine suppression,
such delay is not expected to have clinical significance.
Five hours after a single dosing of oral or injectable octreotide peaked, plasma octreotide levels remained within
therapeutic concentrations (⬎0.5 ng/ml). In addition,
plasma octreotide half-life was comparable between treatments, with an average of 2.5 h measured in both groups.
To inform optimal conditions for oral octreotide dosing, the effects of food and PPI on the PK profile of oral
octreotide were tested. Food had a pronounced effect on
absorption of oral octreotide, inasmuch as there was an
almost 90% reduction in plasma concentrations. A more
moderate effect (40%) was associated with PPI administration before oral octreotide dosing. Full meal and PPI
may reduce octreotide absorption from Octreolin due its
effect on raising gastric pH and emptying (30, 31), causing
dissolution of the pH-dependent enteric-coated Octreolin
capsule in the stomach, rather than in the small intestine
where octreotide absorption occurs. Additionally, the
presence of large quantities of food may obstruct intestinal
wall contact needed for effective octreotide absorption
from Octreolin.
Suppression of GH secretion by oral octreotide dosing
was demonstrated before and after GHRH/arginine infusion in the current study. Somatostatin analogs, such as
octreotide, bind to pituitary somatostatin receptors 2, 5,
and 3 and markedly reduce GH secretion for several hours
(1). Octreotide infusion (0.5 mg) to healthy volunteers
suppressed GH concentrations to below 0.25 ng/ml (7).
Similar inhibitory effect on GH concentrations for injectable octreotide has also been documented in acromegaly
patients (32), associated with a plasma octreotide concentration of approximately 1 ng/ml. In the present study,
plasma concentrations of octreotide 2 h after oral dosing
of 20 mg achieved mean concentrations of approximately
1.75 ng/ml, and mean GH levels in these healthy participants were indeed less than 0.25 ng/ml (Fig. 4B). Conversely, in the nontreated group, serum GH concentrations were approximately 2.75 ng/ml at this time-point.
J Clin Endocrinol Metab, July 2012, 97(7):2362–2369
Moreover, 80% of GH secretion induced by GHRH was
suppressed in the octreotide-treated arm (Fig. 4A). These
results indicate that oral octreotide exhibits a GH-inhibitory action similar to the parenteral drug form in healthy
volunteers.
In conclusion, we have shown that oral delivery of octreotide is feasible, using a unique formulation based on an
oily suspension. This oral octreotide preparation results in
comparable octreotide PK characteristics to sc injection,
achieves levels known to be therapeutic, and exerts a notable suppression of basal as well as GHRH-induced GH
secretion. A major drawback of current treatments is the
need for frequent sc or im injections. The oral formulation
tested here is potentially useful for chronic octreotide
treatment of patients with acromegaly or neuroendocrine
tumors.
Acknowledgments
Address all correspondence and requests for reprints to: Dr. Roni
Mamluk, Ph.D., COO, Chiasma, 10 Hartom Street, Jerusalem
45182, Israel. E-mail: [email protected].
Disclosure Summary: S.T., S.L.T., S.K., P.S., D.P., I.L., I.K.,
and R.M. are Chiasma employees.
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