Adv Ther (2015) 32:650–661 DOI 10.1007/s12325-015-0222-4
ORIGINAL RESEARCH
Pharmacokinetics and Tolerability of Exenatide Delivered by 7-Day Continuous Subcutaneous Infusion in Healthy Volunteers Georgios Vlasakakis . Susan L. Johnson . Jiang Lin . Xiaozhou Yao . Christopher J. Gruenloh . John P. Chism . Derek J. Nunez
To view enhanced content go to www.advancesintherapy.com Received: May 8, 2015 / Published online: July 10, 2015 Springer Healthcare 2015
ABSTRACT
were tested: Constant 24-h infusion (16.5 lg/day),
Introduction: Small peptides are approved as
constant 7-day infusion (25.5 lg/day in Cohort 2), and two different 7-day escalation regimens
treatments for type 2 diabetes mellitus and may
(ranging from 7 to 58.5 lg/day in Cohort 1 and
have utility in metabolic diseases. These peptides often have short half-lives requiring
25.5–58.5 lg/day in Cohort 3). Results: While the overall
delivery either as a sustained-release formulation or via a device. The opportunity
pharmacokinetics were in line with those expected, the observed within-subject
to study their pharmacokinetics using simple
concentration variability was considerable.
solution formulations delivered by continuous subcutaneous infusion may facilitate the drug
Conclusion: Our work identifies sources of potential pharmacokinetic variability relating
development process. Methods: Here, we investigated the systemic
to the method of delivery and the drug’s formulation that will be valuable to
exposure of an exemplar peptide (exenatide)
investigators contemplating the delivery of
when infused in healthy subjects using a Paradigm RevelTM insulin infusion pump
peptides via insulin infusion pumps. Funding: GlaxoSmithKline.
(Medtronic MiniMed). Four infusion regimens
Trial registration: ClinicalTrials.gov number, NCT01857895.
Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0222-4) contains supplementary material, which is available to authorized users. G. Vlasakakis (&) GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, London UB11 1BT, UK e-mail: [email protected] S. L. Johnson J. Lin X. Yao C. J. Gruenloh J. P. Chism D. J. Nunez GlaxoSmithKline Research and Development, 5 Moore Dr, Research Triangle Park, NC, USA
exenatide
Keywords: Exenatide; Glucagon-like peptide-1 (GLP-1); Glucose; Infusion; Insulin pump; Pharmacokinetics; Type 2 diabetes mellitus
INTRODUCTION Peptide-based therapeutic agents are being used more frequently in medical practice because of
Adv Ther (2015) 32:650–661
651
their unique advantages over large proteins,
systemic concentration profile of this drug
including better permeability, a smaller risk of
may
immunogenicity, and a lower manufacturing cost [1, 2]. However, the development of novel
medication, including improved tolerability [14].
small peptides as drug candidates can be challenging because of their low oral
In this study, we have investigated the approach that simple solution formulations
bioavailability and their rapid metabolism by
delivered
plasma and tissue peptidases that make their half-lives relatively short [3]. The glucagon-like
infusion can facilitate the early clinical assessment of potential novel therapeutic
peptide-1 (GLP-1) class used in the management of type 2 diabetes mellitus (T2DM) is a good
peptides with short half-lives. As the only clinical data available following a
representation
subcutaneous
of
this
class
of
peptide
change
the
by
overall
profile
continuous
infusion
of
of
the
subcutaneous
exenatide
are
therapeutics. Their pharmacological actions include a dose-dependent stimulation of
restricted to a 24-h constant-rate infusion [11], we exploited model-based predictions to
insulin secretion, suppression of pancreatic glucagon release, a reduction of appetite and
provide dose recommendations (based on infusion rate) prior to the initiation of each
food intake, and a slowing of gastric emptying
part of the study to achieve targeted clinical
[4, 5], as well as promotion of proliferation and islet neogenesis,
exposures for exenatide.
b-cell both
in vitro [6] and in vivo [7], and restoration of insulin secretion in patients with T2DM [8]. Exenatide (Byetta, AstraZeneca) is a synthetic analog of endogenous GLP-1 that
METHODS Study Participants and Design
binds to GLP-1 receptors to produce the pharmacological effects noted above. It is administered twice daily by subcutaneous injection using a pre-filled pen that delivers either 5 or 10 lg of the drug. It is moderately resistant to plasma and tissue peptidases conferring a half-life of approximately 120 min in the human circulation when administered subcutaneously [3]. Following the administration of bolus injections of Byetta in human studies, nausea and vomiting have been reported as adverse events (AEs) in a significant proportion of healthy subjects and patients with T2DM [9, 10]. However, a newer delivery system, exemplified by Bydureon (AstraZeneca), provides once-weekly sustainedrelease delivery that achieves steady state after approximately 6 weeks [14]. This sustained release has shown that modification of the
The study protocol and one amendment, the informed consent, and other relevant information were reviewed and approved by a GlaxoSmithKline protocol review group and an institutional review board (Aspireirb, 11491 Woodside Ave, Santee, CA 92071), in accordance with the International Conference on Harmonization Good Clinical Practice guidelines
and
the
principles
of
the
Declaration of Helsinki. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. This study was registered at www. clinicaltrials.gov
(ClinicalTrials.gov
number,
NCT01857895). The demographic and baseline characteristics of the study population are shown in Table S1 in the electronic supplementary material (ESM).
Adv Ther (2015) 32:650–661
652
In Part A of the study, two healthy subjects (subject
3001
and
3002)
received
24-h
subcutaneous infusions of exenatide (16.5 lg/day) that were predicted to achieve a maximum concentration (Cmax) of approximately 100 pg/mL. This 100 pg/mL concentration of exenatide was well tolerated in a published continuous-infusion study [11]. Pharmacokinetic (PK) data from Part A were compared to model-predicted exposures to assess whether an update of the model was required before proceeding to dose predictions for the infusion paradigms in Part B. Part B was designed to evaluate
the
escalation of the infusion rate of exenatide in healthy subjects, as well as to test the impact on the PK from changes of the infusion sets. The initial plan was for six healthy subjects to receive subcutaneous infusions of exenatide for a maximum of 7 days. Based on the emergent PK data during the study, the cohort structure and the doses in Part B were adjusted within the flexibility allowed by the protocol, and the number of the subjects was increased to eight. Based on the model’s predictions, the maximal plasma concentrations to be achieved during infusions were not anticipated to exceed the mean steady-state concentration levels
produce
a
300 pg/mL. Subjects in
mean Part
steady-state B
were
level
of
administered
exenatide doses as described in Table 1. Plasma samples for measurement
of
exenatide concentration were drawn at times 0, 0.5, 1, 2, 4, 6, 10, 14, 24 h in Part A, and at times 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 10, and 14 h for Days 1 and 2, and 0, 0.5, 1, 2, 3, 4, 6, 10, and 14 h for Days 3–7 in Part B. Time 0 was immediately prior to the time of infusion rate start or adjustment. In Part A, two additional samples were drawn at 26 and 28 h to ensure that clearance of exenatide was consistent with the reported value in the Byetta label [15]. For both Part A and B, subjects who met all screening criteria (see Section 1 in the ESM) were admitted to the clinic on Day -1 for baseline procedures. Exenatide infusion began on the morning of Day 1 and continued for a maximum of 7 days. Subjects were discharged from the clinic on Day 2 for Part A and on Day 8 for Part B, and returned for a follow-up visit 8–12 days after discharge. A full schematic of the study design is illustrated in Figure S1 in the ESM. Assays
reported for Bydureon at its approved dose of 2 mg weekly (approximately 300 pg/mL ± 95% confidence interval [CI] 117–450 pg/mL). The actual doses administered in Part B were as follows: • Dose Cohort 1: Two subjects (subjects 3003 and 3004) received an escalating seven-day infusion with a different dose on each day; •
•
Dose Cohort 2: Two subjects (subjects 3005 and 3006) received a single dose without escalation; Dose Cohort 3: Four subjects (subjects 3007–3010) received a two-dose escalation to explore a high dose anticipated to
Blood was collected into K2 EDTA tubes that contained aprotinin (0.1 mg/mL of blood). Plasma samples were analyzed for exenatide concentration using a validated analytical method. The method was based on protein precipitation using trifluoroethanol/ethanol/ acetonitrile/formic acid (5:25:50:0.1 v/v/v/v), followed by high-performance liquid chromatography with two-dimensional column-switching and detection by tandem mass
spectrometry
using
positive
ion
electrospray. The range of the assay was from 10 to 1000 pg/mL.
Adv Ther (2015) 32:650–661
653
Table 1 Part B dosing algorithm Dose (lg/day)
Dose (lg/h)
Actual doses in Dose Cohort 1 (2 subjects) Level 1
Day 1
7.5
0.3125
Level 2
Day 2
16.5
0.6875
Level 3
Day 3
25.5
1.0625
Level 4
Day 4
33
1.375p
Level 5
Day 5
42
1.75
Level 6
Day 6
51
2.125
Level 7
Day 7
58.5
2.4375
25.5
1.0625
Actual dose in Dose Cohort 2 (2 subjects) Level 1
Days 1–7
Actual doses in Dose Cohort 3 (4 subjects) Level 1
Days 1–2
25.5
1.0625
Level 2
Days 3–7
58.5
2.4375
The inter- and intra-assay precision, based on
(Medtronic MiniMed) over periods of no more
percentage coefficient of variability, was \10% and \13%, respectively. The inter- and intra-
than 72 h. Following this period, the transfer process of the Byetta to the reservoir was
assay accuracy, based on percentage difference
repeated with new reservoirs/catheters and
from theoretical, ranged from -4.9% to -3.2% and from -15% to 3.4%, respectively.
administration proceeded via a new injection site.
Medication, Infusion Pump,
PK Model
and Consumables In the absence of published data from longExenatide was commercially sourced as Byetta
lasting exenatide subcutaneous infusions, a PK
and supplied as exenatide 250 lg/mL. It was packaged in a sterile pre-filled pen containing
model was constructed in Berkeley MadonnaTM to guide the infusion rates of exenatide prior to
1.2 or 2.4 mL of drug product [15]. For this study, the exenatide solution was transferred by
each part of the study. As a result, the predicted exenatide exposures could be visualized
the clinical unit pharmacist to the insulin pump
together with the associated between-subject
cartridge without dilution. Filled reservoirs (Medtronic 3.0 mL Reservoir, MMT-332A), Mio
variability (BSV; in the form of a 95% CI) prior to each infusion.
catheters (Medtronic, MMT-965) were dispensed to the clinical unit for continuous
A two-compartment PK model was used to describe the distribution and elimination of
subcutaneous administration using Paradigm
exenatide with the relevant PK parameters fixed
Real-Time Revel
TM
insulin infusion pumps
to the ones reported in the Byetta prescribing
Adv Ther (2015) 32:650–661
654
information [15] document (volume at the
[= 100 9 (sqrt(exp(SD2)-1)), where SD is the
central compartment; Vc = 28.3 L, clearance;
SD of the log-transformed data].
CL = 9.1 L/h). The flow of exenatide from the subcutaneous space into the central compartment was characterized by a first-order absorption with a rate ka = 0.8 h-1. As ka is the most uncertain parameter in the model’s inputs, it was assigned the largest degree of BSV equal to 50%, in contrast to the other two PK parameters that were allocated a rather conservative 30% BSV.
RESULTS Overall, four investigated in
infusion regimens were healthy subjects: Part A
constant 24-h infusion, Part B constant 7-day infusion, and two different 7-day escalation regimens in three different dose cohorts.
Statistical Analysis
Part A: 24-Hour Infusion
The following PK parameters were determined from the plasma concentration–time data for
This part of the study was designed to build
exenatide. The PK parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin (CertaraTM). All
Version 5.2 calculations
or higher of non-
compartmental parameters were based on actual sampling times. • Part A: Area under the concentration–time curve (AUC0–24h), maximum concentration (Cmax0–24h), average concentration calculated by averaging the concentrations measured during the infusion (Cavg0–24h);
confidence around the model-derived predictions that were expected to be in line with short infusion (24 h) published data [11]. Administration of exenatide resulted in a gradual increase in plasma concentrations in both subjects. In subject 3001, this was followed by a secondary peak in concentration with a Cmax of 190 pg/mL, whereas subject 3002 showed a steady-state profile with an average concentration of 72 pg/mL. Table S2 in the ESM provides a detailed summary parameters for each subject.
of
the
PK
The averaged mean (%CV) Cavg during the
Part B: AUC0–24h, Cmax0–24h, Cavg0–24h, for each of the 7 days, and AUC0–168h,
entire infusion was similar to the predicted value of 50 pg/mL, being 77.5 (8) pg/mL for
Cmax0–168h, Cavg0–168h infusion period.
entire
subjects 3001 and 3002. However, both PK profiles had concentration peaks that well
For each of these parameters, the following
exceeded the upper limit of the modeling
summary statistics were calculated by treatment group: Median, maximum, minimum, averaged
predictions. In subject 3001, there was a suspension of the pump that occurred
mean, standard deviation (SD), between-subject coefficient of variation for the untransformed
approximately 8 h following the initiation of the infusion and which lasted for 5 min.
data (= 100 9 [SD/mean]), geometric
Individual
•
over
the
mean,
concentration–time
profiles
for
95% CI for the geometric mean, SD of logarithmically transformed data, and the
subject 3001 and subject 3002 following 24-h infusion of 16.5 lg/day of exenatide are
between-subject coefficient of variation (%CV) for the log-transformed data
displayed in Fig. 1, together with the time of the pump’s suspension.
Adv Ther (2015) 32:650–661
655
Fig. 1 Exenatide plasma concentration–time profiles after continuous infusion of 16.5 lg/day of exenatide for 24 h (Part A). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked solid lines the clinical Part B: Dose Cohort 1
For subject 3003, there were two reservoir
For the next part exenatide, PK was investigated when subjects received progressively higher infusion rates. Individual concentration–time profiles for subject 3003 and subject 3004 following a 7-day escalating infusion (7.5 lg/day on Day 1, 16.5 lg/day on Day 2, 25.5 lg/day on Day 3, 33 lg/day on Day 4, 42 lg/day on Day 5, 51 lg/day on Day 6, and 58.5 lg/day on Day 7) are displayed in Fig. 2. The dose-escalation paradigm resulted in daily increases in plasma concentrations in both subjects. On Day 1, the exposure had a high peak with an averaged mean (%CV) Cmax0–24h of 106 (18) pg/mL that was consistent between the two subjects. The exposure reached a Cmax of 168 pg/mL on Day 6 for subjects 3003 and 145 pg/mL on Day 7 for subject 3004. The averaged
mean
(%CV)
exenatide observations for subjects 3001 and 3002 as shown in the legend. Blue vertical dashed line shows where pump suspension occurred for subject 3001 (there was no pump suspension event recorded for subject 3002). HRS hours
Cmax0–168h
156.5 (16) pg/mL, almost identical model-predicted value of 150 pg/mL.
to
replacements on Days 3 and 6, each lasting for approximately 20 min. In addition, on the night of Day 6, the infusion was interrupted for several hours (the exact number of hours was not recorded) due to the detachment of the infusion set. Reservoir replacements occurred on the same days for subject 3004 and with a similar duration. A detailed representation of the areas where the pump was suspended can be found in Fig. 2. Table S3 in the ESM provides a detailed summary of the PK parameters for each subject. Part B: Dose Cohort 2 The manufacturer of the insulin infusion system used in this study recommends
was
replacement of the insulin reservoir and delivery system every 3 days. To differentiate
the
the effect on the PK of exenatide following reservoir replacement and catheter changes
656
Adv Ther (2015) 32:650–661
Fig. 2 Exenatide plasma concentration–time profiles after a 7-day continuous infusion where infusion rates were escalated on the morning of each day (Part B Dose Cohort 1). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the
mean. Symbol-marked solid lines the observed exenatide concentrations for subjects 3003 and 3004, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (blue for subject 3003 and red for subject 3004). HRS hours
from those due to changes in the infusion rates, a 7-day constant-rate infusion paradigm was
A constant-rate infusion of exenatide resulted in a gradual increase in plasma
used in this dose cohort. Individual concentration–time profiles for subjects 3005
concentrations followed by a steady-state phase that was maintained until the end of
and 3006 following a 7-day constant-rate
the infusion. The observed Cmax0–168h values
infusion of 25.5 lg/day are displayed in Fig. 3.
were 220 and 162 pg/mL, and the Cavg0–168h
Fig. 3 Exenatide plasma concentration–time profiles after a 7-day continuous constant infusion with a fixed rate (Part B Dose Cohort 2). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked solid lines the
clinical exenatide observations for subjects 3005 and 3006, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (blue for subject 3005 and red for subject 3006). HRS hours
Adv Ther (2015) 32:650–661
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values were 143.3 and 113.7 pg/mL for subjects
58.5 lg/day to target exenatide exposures near
3005 and 3006, respectively. For subject 3006,
300 pg/mL.
there was a significant drop in plasma concentration in the afternoon of Day 2 (at
The individual concentration–time profiles for subjects 3007, 3008, 3009, and 3010
approximately 28 h) which only recovered after the scheduled reservoir replacement on Day 3.
following constant
In addition to this, there were two planned
together with the suspensions intervals of the
suspensions for reservoir replacements that occurred on Days 3 and 6 in both subjects.
insulin infusion pumps, are shown in Fig. 4. A constant infusion of exenatide during the first
There were a few additional interruptions when the subjects took a shower or for changes in the
48 h resulted in an averaged mean (%CV) Cavg0–48h of 119 (26) pg/mL. The infusion rate
infusion sets which are all depicted in Fig. 3.
was increased on the morning of Day 3 (at
The constant infusion of exenatide for 7 days resulted in Cavg0–168h and AUC0–168h values that
approximately 49 h) and remained constant until the end of the infusion. Post-Day 3, the
were similar for subjects 3005 and 3006. The averaged mean (%CV) Cavg0–168h was
averaged mean (%CV) Cavg48–168h was 343 (71) pg/mL. There were some fluctuations
128.5 (21) pg/mL, and this was similar to the
around the steady state in the form of high
model-predicted value of 150 pg/mL. Despite the drop in the exposure of subject 3006, there
peaks. More specifically, subject 3010 reached a transient peak exposure towards the end of the
were only minor fluctuations around the steady-state concentrations. Overall, the
infusion of approximately 700 pg/mL, which, interestingly, occurred followed the change in
reduced number of infusion rate changes seemed to result in a more stable PK profile
infusion sets. Subject 3010 presented a similar magnitude of exposure, but this was more
that followed the model’s predictions from Day
prolonged;
3 to the end of the study. Table S4 in the ESM provides a detailed summary of the PK
remains unclear. Suspensions of the infusions occurred on Days 3 and 6 in all four subjects
information for each subject.
that lasted for approximately 20 min (at approximately 54 and 126 h). In addition to
Part B: Dose Cohort 3
these, there were a few times when the infusion
In the last part of the study, a mixed constant
was interrupted, as demonstrated in Fig. 4. The constant-rate infusion of 25.5 lg/day
and escalating regimen was used to investigate further the PK variability at higher infusion
exenatide during the first two days resulted in an averaged mean (%CV) Cavg0–48h of
rates that were predicted to achieve concentrations comparable to the mean
119 (26) pg/mL that was close to the model’s
a 7-day infusion
the
mixed escalating and of 25.5–58.5 lg/day,
reason
for
this
duration
approved steady-state concentration reported
predicted value of 150 pg/mL. The Cavg0–48h in this part was also similar to the Cavg0–168h from
for Bydureon (300 pg/mL). A secondary aim was to test an infusion-modification algorithm,
Part B Dose Cohort 2 (119 vs. 128.5 pg/mL, respectively) which used the same constant
should a subject develop nausea and/or vomiting. The infusion rate was kept at
infusion rate over 7 days. The averaged mean
25.5 lg/day for the first 2 days, and in the
concentration from Day 3 until the end of the infusion Cavg48–168h was approximately
morning
343 (71) pg/mL. This is in good agreement
of
Day
3
it
was
increased
to
Adv Ther (2015) 32:650–661
658
Fig. 4 Exenatide plasma concentration–time profiles after a 7-day continuous constant infusion with mixed escalating and fixed rate (Part B Dose Cohort 3). Solid line the modelpredicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked
solid lines the clinical exenatide observations for subjects 3007–3010, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (dark blue for subject 3007, red for subject 3008, light blue for subject 3009, and yellow for subject 3010). HRS hours
with the model’s predicted value of 300 pg/mL. Subjects 3007 and 3010 had the highest overall
subject had a mild AE of nausea and another had a mild event of decreased appetite.
54,456 pg h/mL,
There were no meaningful changes with
respectively, due to a transient high concentration peak towards the end of the
therapy in hematological, chemistry, or urinalysis parameters. Consistent with known
infusion. It was noticeable that the PK profile was very stable during the first two days for all
effects of exenatide [14, 15], values for blood pressure most often decreased with therapy and
four subjects compared to the first two days in
values for heart rate most often increased with
Part B Dose Cohort 2 that used the same infusion rate, but no explanation was found.
treatment. However, there were no measurements meeting criteria for potential
Table S5 in the ESM provides a detailed summary of the PK information for each
clinical importance.
AUC0–168h
of
64,858
and
subject.
DISCUSSION Safety There were no AEs in Part A of the study. In Part
Peptides of potential therapeutic interest with a short half-life may require a delivery technology
B, there were three AEs; none were considered serious or led to withdrawal from the study.
or a complex formulation to provide an effective, patient-friendly dosing regimen. The
One subject in Dose Cohort 2 experienced two
opportunity to study the PK behavior of these
AEs: mild abdominal discomfort and mild decreased appetite. In Dose Cohort 3, one
peptides using simple solution formulations delivered by an insulin pump may facilitate
Adv Ther (2015) 32:650–661
659
the early understanding of safety, tolerability,
been established may lead to more consistent
and their pharmacodynamic (PD) properties.
data. Second, there were occasional periods in
The current study was designed to examine the feasibility of delivering exenatide, as an
individual subjects where exposure levels were low. We hypothesize that the method of filling
exemplar peptide, via continuous subcutaneous infusion using an insulin pump. In addition, as
the reservoir by actuation of the Byetta pen, rather than filling from a glass vial under
there are very limited concentration data in the
pressure, may have allowed bubbles to enter
literature from infusion studies, our aim was to guide the doses (infusion rates) using model-
the system to a greater degree. When we targeted the mean exposure
based predictions. Overall, the model, particularly using the final 7-day infusions,
observed with Bydureon, we were interested in evaluating the safety and tolerability of
accurately predicted the mean PK parameters
delivering a continuous infusion of exenatide,
(i.e., Cmax, Cavg, AUC), although the observed within-subject variability was considerable. The
and particularly of adjusting the infusion rate to manage gastrointestinal AEs. The exenatide
limited numbers of volunteers do not allow robust statements on the BSV, although this was
slow-release formulation (Bydureon) has a reported steady-state exposure of 300 pg/mL
captured and reported in this study.
after 6 weeks of dosing 2 mg once weekly [14].
While the overall data supported the feasibility of this study methodology, there are
In Phase III studies of Bydureon, nausea was reported as an adverse event in approximately
several observations that are important. Qualitative assessment suggested that there
10–25% of subjects [14]. In the studies by Henry and colleagues [12, 13], an implantable device
was greater than anticipated within-subject variability. Insulin pumps are designed and
delivered a slow infusion of exenatide to patients with T2DM and achieved a
regulated to provide a precise subcutaneous
concentration profile similar to that seen in
insulin infusion, and thus it may be presumed that some part of the observed exenatide
the final dose cohort of the present study at the highest infusion rate. In the high dose group of
concentration variability was unique to the formulation used. Several observations may be
that study, 20% of subjects had nausea and/or vomiting after 1 week of treatment. After
useful to consider regarding the variability.
2 weeks,
First, increased concentrations were often noted at the time of pump initiation and at
experienced nausea and 80% experienced vomiting. In contrast, in our study, we had
the time of reservoir replacements (Figs. 1, 2, 3, 4). In addition, this observation also explains
few reported gastrointestinal events and these were mild and short-lived, and they did not
the deviation of the model-predicted PK for the
require treatment or an adjustment of the
initial 24-h infusion in the first cohort as well as Part B Cohorts. The deviations noted at this
infusion rate. The proportion of subjects having gastrointestinal events in the present
time seemed to be independent of dose, suggesting that more dilute concentrations of
study was lower than might have been anticipated from the literature and could be
a peptide could reduce PK variability. In
due to enrolling, by chance, subjects with less
addition, the practice of changing catheters and ceasing infusions for activities such as
sensitivity to nausea or, alternatively, to differences in sensitivity between healthy
showers during times where steady state has
subjects and patients with T2DM. It is also
approximately
40%
of
subjects
Adv Ther (2015) 32:650–661
660
possible that there may be something unique to the pump infusion paradigm we employed that
whole, and have given final approval for the version to be published.
led to the differences in the tolerability profile. Conflict of interest. Georgios Vlasakakis was an employee of GlaxoSmithKline at the time of
CONCLUSIONS We
have
demonstrated
this the
feasibility
of
utilizing insulin pumps to provide continuous subcutaneous infusion of a peptide, as well as the utility of model predictions to make dose recommendations in the early clinical development of novel peptides. This type of a study can be used as a proof-of-principle to investigate novel peptides in humans which are less
well
characterized
than
exenatide.
publication
and
has/had
stock/stock
options in the company. Susan L. Johnson was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Jiang Lin was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Xiaozhou Yao was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock
Sustained delivery using an infusion pump allows control and flexibility when
options in Gruenloh
the company. Christopher J. was an employee of
investigating PK/PD, while ensuring subject safety because of the ability to modify the
GlaxoSmithKline
at
the
time
of
this
infusion regimen. However, there are some
publication and has/had stock/stock options in the company. John P. Chism was an employee
notable limitations, particularly the observed within-subject variability, which should be
of GlaxoSmithKline at the time of this publication and has/had stock/stock options in
considered when designing a study for a novel peptide and interpreting the resulting study
the company. Derek J. Nunez was an employee
data.
of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company.
ACKNOWLEDGMENTS
Compliance
with ethics guidelines. The
study protocol and one amendment, the
This study (ClinicalTrials.gov number, NCT01857895) and the article processing
informed consent, and other relevant information were reviewed and approved by a
charges associated with this publication have
GlaxoSmithKline protocol review group and an institutional review board (Aspireirb, 11491
been sponsored by GlaxoSmithKline. We thank the investigator and subjects who participated
Woodside
Ave,
Santee,
CA
92071),
in
in the study and Rebecca Hodge, Ella Kersey, Malcolm Young, and Steve Stagliano
accordance with the International Conference on Harmonization Good Clinical Practice
(Medtronic Inc.) for their valuable input. All
guidelines and the principles of the Declaration of Helsinki. Written informed
named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a
consent was obtained from each subject prior to the performance of any study-specific procedures.
Adv Ther (2015) 32:650–661
661
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Diao L, Meibohm B. Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Correlations of Therapeutic Peptides. Clin Pharmacokinet. 2013;52:855–68.
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Nauck MA. GLP-1 for the treatment of type 2 diabetes. Horm Metab Res. 2004;36:852–8.
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De Silva A, Salem hormones PYY3–36 food intake and appetite centers 2011;14:1–7.
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Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117:77–88.
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V, Long CJ, et al. The gut and GLP-17–36 amide reduce modulate brain activity in in humans. Cell Metab.
Gedulin BR, Nikoulina SE, Smith PA, et al. Exenatide (exendin-4) improves insulin sensitivity and b-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology. 2005;146:2069–76. Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments first and second phase insulin secretion in response to intravenous glucose in subjects with
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DeFronzo RA, Ratner R, Han J, Kim DD, Fineman MS, Baron AD. Effect of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–100.
10. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083–91. 11. Taylor K, Kim D, Nielsen LL, Aisporna M, Baron AD, Fineman MS. Day-long subcutaneous infusion of exenatide lowers glycemia in patients with type 2 diabetes. Horm Metab Res. 2005;37:627–32. 12. Henry RR, Rosenstock J, Logan DK, Alessi TR, Luskey K, Baron MA. Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. Diabetes Care. 2013;36:2559–65. 13. Henry RR, Rosenstock J, Logan D, et al. Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complicat. 2014;28(3):393–8. 14. Bydureon Package Insert. https://www.bydureon. com/. Accessed 20 June 2015. 15. Byetta Package Insert. https://www.byetta.com/. Accessed 20 June 2015.
ORIGINAL RESEARCH
Pharmacokinetics and Tolerability of Exenatide Delivered by 7-Day Continuous Subcutaneous Infusion in Healthy Volunteers Georgios Vlasakakis . Susan L. Johnson . Jiang Lin . Xiaozhou Yao . Christopher J. Gruenloh . John P. Chism . Derek J. Nunez
To view enhanced content go to www.advancesintherapy.com Received: May 8, 2015 / Published online: July 10, 2015 Springer Healthcare 2015
ABSTRACT
were tested: Constant 24-h infusion (16.5 lg/day),
Introduction: Small peptides are approved as
constant 7-day infusion (25.5 lg/day in Cohort 2), and two different 7-day escalation regimens
treatments for type 2 diabetes mellitus and may
(ranging from 7 to 58.5 lg/day in Cohort 1 and
have utility in metabolic diseases. These peptides often have short half-lives requiring
25.5–58.5 lg/day in Cohort 3). Results: While the overall
delivery either as a sustained-release formulation or via a device. The opportunity
pharmacokinetics were in line with those expected, the observed within-subject
to study their pharmacokinetics using simple
concentration variability was considerable.
solution formulations delivered by continuous subcutaneous infusion may facilitate the drug
Conclusion: Our work identifies sources of potential pharmacokinetic variability relating
development process. Methods: Here, we investigated the systemic
to the method of delivery and the drug’s formulation that will be valuable to
exposure of an exemplar peptide (exenatide)
investigators contemplating the delivery of
when infused in healthy subjects using a Paradigm RevelTM insulin infusion pump
peptides via insulin infusion pumps. Funding: GlaxoSmithKline.
(Medtronic MiniMed). Four infusion regimens
Trial registration: ClinicalTrials.gov number, NCT01857895.
Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0222-4) contains supplementary material, which is available to authorized users. G. Vlasakakis (&) GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, London UB11 1BT, UK e-mail: [email protected] S. L. Johnson J. Lin X. Yao C. J. Gruenloh J. P. Chism D. J. Nunez GlaxoSmithKline Research and Development, 5 Moore Dr, Research Triangle Park, NC, USA
exenatide
Keywords: Exenatide; Glucagon-like peptide-1 (GLP-1); Glucose; Infusion; Insulin pump; Pharmacokinetics; Type 2 diabetes mellitus
INTRODUCTION Peptide-based therapeutic agents are being used more frequently in medical practice because of
Adv Ther (2015) 32:650–661
651
their unique advantages over large proteins,
systemic concentration profile of this drug
including better permeability, a smaller risk of
may
immunogenicity, and a lower manufacturing cost [1, 2]. However, the development of novel
medication, including improved tolerability [14].
small peptides as drug candidates can be challenging because of their low oral
In this study, we have investigated the approach that simple solution formulations
bioavailability and their rapid metabolism by
delivered
plasma and tissue peptidases that make their half-lives relatively short [3]. The glucagon-like
infusion can facilitate the early clinical assessment of potential novel therapeutic
peptide-1 (GLP-1) class used in the management of type 2 diabetes mellitus (T2DM) is a good
peptides with short half-lives. As the only clinical data available following a
representation
subcutaneous
of
this
class
of
peptide
change
the
by
overall
profile
continuous
infusion
of
of
the
subcutaneous
exenatide
are
therapeutics. Their pharmacological actions include a dose-dependent stimulation of
restricted to a 24-h constant-rate infusion [11], we exploited model-based predictions to
insulin secretion, suppression of pancreatic glucagon release, a reduction of appetite and
provide dose recommendations (based on infusion rate) prior to the initiation of each
food intake, and a slowing of gastric emptying
part of the study to achieve targeted clinical
[4, 5], as well as promotion of proliferation and islet neogenesis,
exposures for exenatide.
b-cell both
in vitro [6] and in vivo [7], and restoration of insulin secretion in patients with T2DM [8]. Exenatide (Byetta, AstraZeneca) is a synthetic analog of endogenous GLP-1 that
METHODS Study Participants and Design
binds to GLP-1 receptors to produce the pharmacological effects noted above. It is administered twice daily by subcutaneous injection using a pre-filled pen that delivers either 5 or 10 lg of the drug. It is moderately resistant to plasma and tissue peptidases conferring a half-life of approximately 120 min in the human circulation when administered subcutaneously [3]. Following the administration of bolus injections of Byetta in human studies, nausea and vomiting have been reported as adverse events (AEs) in a significant proportion of healthy subjects and patients with T2DM [9, 10]. However, a newer delivery system, exemplified by Bydureon (AstraZeneca), provides once-weekly sustainedrelease delivery that achieves steady state after approximately 6 weeks [14]. This sustained release has shown that modification of the
The study protocol and one amendment, the informed consent, and other relevant information were reviewed and approved by a GlaxoSmithKline protocol review group and an institutional review board (Aspireirb, 11491 Woodside Ave, Santee, CA 92071), in accordance with the International Conference on Harmonization Good Clinical Practice guidelines
and
the
principles
of
the
Declaration of Helsinki. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. This study was registered at www. clinicaltrials.gov
(ClinicalTrials.gov
number,
NCT01857895). The demographic and baseline characteristics of the study population are shown in Table S1 in the electronic supplementary material (ESM).
Adv Ther (2015) 32:650–661
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In Part A of the study, two healthy subjects (subject
3001
and
3002)
received
24-h
subcutaneous infusions of exenatide (16.5 lg/day) that were predicted to achieve a maximum concentration (Cmax) of approximately 100 pg/mL. This 100 pg/mL concentration of exenatide was well tolerated in a published continuous-infusion study [11]. Pharmacokinetic (PK) data from Part A were compared to model-predicted exposures to assess whether an update of the model was required before proceeding to dose predictions for the infusion paradigms in Part B. Part B was designed to evaluate
the
escalation of the infusion rate of exenatide in healthy subjects, as well as to test the impact on the PK from changes of the infusion sets. The initial plan was for six healthy subjects to receive subcutaneous infusions of exenatide for a maximum of 7 days. Based on the emergent PK data during the study, the cohort structure and the doses in Part B were adjusted within the flexibility allowed by the protocol, and the number of the subjects was increased to eight. Based on the model’s predictions, the maximal plasma concentrations to be achieved during infusions were not anticipated to exceed the mean steady-state concentration levels
produce
a
300 pg/mL. Subjects in
mean Part
steady-state B
were
level
of
administered
exenatide doses as described in Table 1. Plasma samples for measurement
of
exenatide concentration were drawn at times 0, 0.5, 1, 2, 4, 6, 10, 14, 24 h in Part A, and at times 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 10, and 14 h for Days 1 and 2, and 0, 0.5, 1, 2, 3, 4, 6, 10, and 14 h for Days 3–7 in Part B. Time 0 was immediately prior to the time of infusion rate start or adjustment. In Part A, two additional samples were drawn at 26 and 28 h to ensure that clearance of exenatide was consistent with the reported value in the Byetta label [15]. For both Part A and B, subjects who met all screening criteria (see Section 1 in the ESM) were admitted to the clinic on Day -1 for baseline procedures. Exenatide infusion began on the morning of Day 1 and continued for a maximum of 7 days. Subjects were discharged from the clinic on Day 2 for Part A and on Day 8 for Part B, and returned for a follow-up visit 8–12 days after discharge. A full schematic of the study design is illustrated in Figure S1 in the ESM. Assays
reported for Bydureon at its approved dose of 2 mg weekly (approximately 300 pg/mL ± 95% confidence interval [CI] 117–450 pg/mL). The actual doses administered in Part B were as follows: • Dose Cohort 1: Two subjects (subjects 3003 and 3004) received an escalating seven-day infusion with a different dose on each day; •
•
Dose Cohort 2: Two subjects (subjects 3005 and 3006) received a single dose without escalation; Dose Cohort 3: Four subjects (subjects 3007–3010) received a two-dose escalation to explore a high dose anticipated to
Blood was collected into K2 EDTA tubes that contained aprotinin (0.1 mg/mL of blood). Plasma samples were analyzed for exenatide concentration using a validated analytical method. The method was based on protein precipitation using trifluoroethanol/ethanol/ acetonitrile/formic acid (5:25:50:0.1 v/v/v/v), followed by high-performance liquid chromatography with two-dimensional column-switching and detection by tandem mass
spectrometry
using
positive
ion
electrospray. The range of the assay was from 10 to 1000 pg/mL.
Adv Ther (2015) 32:650–661
653
Table 1 Part B dosing algorithm Dose (lg/day)
Dose (lg/h)
Actual doses in Dose Cohort 1 (2 subjects) Level 1
Day 1
7.5
0.3125
Level 2
Day 2
16.5
0.6875
Level 3
Day 3
25.5
1.0625
Level 4
Day 4
33
1.375p
Level 5
Day 5
42
1.75
Level 6
Day 6
51
2.125
Level 7
Day 7
58.5
2.4375
25.5
1.0625
Actual dose in Dose Cohort 2 (2 subjects) Level 1
Days 1–7
Actual doses in Dose Cohort 3 (4 subjects) Level 1
Days 1–2
25.5
1.0625
Level 2
Days 3–7
58.5
2.4375
The inter- and intra-assay precision, based on
(Medtronic MiniMed) over periods of no more
percentage coefficient of variability, was \10% and \13%, respectively. The inter- and intra-
than 72 h. Following this period, the transfer process of the Byetta to the reservoir was
assay accuracy, based on percentage difference
repeated with new reservoirs/catheters and
from theoretical, ranged from -4.9% to -3.2% and from -15% to 3.4%, respectively.
administration proceeded via a new injection site.
Medication, Infusion Pump,
PK Model
and Consumables In the absence of published data from longExenatide was commercially sourced as Byetta
lasting exenatide subcutaneous infusions, a PK
and supplied as exenatide 250 lg/mL. It was packaged in a sterile pre-filled pen containing
model was constructed in Berkeley MadonnaTM to guide the infusion rates of exenatide prior to
1.2 or 2.4 mL of drug product [15]. For this study, the exenatide solution was transferred by
each part of the study. As a result, the predicted exenatide exposures could be visualized
the clinical unit pharmacist to the insulin pump
together with the associated between-subject
cartridge without dilution. Filled reservoirs (Medtronic 3.0 mL Reservoir, MMT-332A), Mio
variability (BSV; in the form of a 95% CI) prior to each infusion.
catheters (Medtronic, MMT-965) were dispensed to the clinical unit for continuous
A two-compartment PK model was used to describe the distribution and elimination of
subcutaneous administration using Paradigm
exenatide with the relevant PK parameters fixed
Real-Time Revel
TM
insulin infusion pumps
to the ones reported in the Byetta prescribing
Adv Ther (2015) 32:650–661
654
information [15] document (volume at the
[= 100 9 (sqrt(exp(SD2)-1)), where SD is the
central compartment; Vc = 28.3 L, clearance;
SD of the log-transformed data].
CL = 9.1 L/h). The flow of exenatide from the subcutaneous space into the central compartment was characterized by a first-order absorption with a rate ka = 0.8 h-1. As ka is the most uncertain parameter in the model’s inputs, it was assigned the largest degree of BSV equal to 50%, in contrast to the other two PK parameters that were allocated a rather conservative 30% BSV.
RESULTS Overall, four investigated in
infusion regimens were healthy subjects: Part A
constant 24-h infusion, Part B constant 7-day infusion, and two different 7-day escalation regimens in three different dose cohorts.
Statistical Analysis
Part A: 24-Hour Infusion
The following PK parameters were determined from the plasma concentration–time data for
This part of the study was designed to build
exenatide. The PK parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin (CertaraTM). All
Version 5.2 calculations
or higher of non-
compartmental parameters were based on actual sampling times. • Part A: Area under the concentration–time curve (AUC0–24h), maximum concentration (Cmax0–24h), average concentration calculated by averaging the concentrations measured during the infusion (Cavg0–24h);
confidence around the model-derived predictions that were expected to be in line with short infusion (24 h) published data [11]. Administration of exenatide resulted in a gradual increase in plasma concentrations in both subjects. In subject 3001, this was followed by a secondary peak in concentration with a Cmax of 190 pg/mL, whereas subject 3002 showed a steady-state profile with an average concentration of 72 pg/mL. Table S2 in the ESM provides a detailed summary parameters for each subject.
of
the
PK
The averaged mean (%CV) Cavg during the
Part B: AUC0–24h, Cmax0–24h, Cavg0–24h, for each of the 7 days, and AUC0–168h,
entire infusion was similar to the predicted value of 50 pg/mL, being 77.5 (8) pg/mL for
Cmax0–168h, Cavg0–168h infusion period.
entire
subjects 3001 and 3002. However, both PK profiles had concentration peaks that well
For each of these parameters, the following
exceeded the upper limit of the modeling
summary statistics were calculated by treatment group: Median, maximum, minimum, averaged
predictions. In subject 3001, there was a suspension of the pump that occurred
mean, standard deviation (SD), between-subject coefficient of variation for the untransformed
approximately 8 h following the initiation of the infusion and which lasted for 5 min.
data (= 100 9 [SD/mean]), geometric
Individual
•
over
the
mean,
concentration–time
profiles
for
95% CI for the geometric mean, SD of logarithmically transformed data, and the
subject 3001 and subject 3002 following 24-h infusion of 16.5 lg/day of exenatide are
between-subject coefficient of variation (%CV) for the log-transformed data
displayed in Fig. 1, together with the time of the pump’s suspension.
Adv Ther (2015) 32:650–661
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Fig. 1 Exenatide plasma concentration–time profiles after continuous infusion of 16.5 lg/day of exenatide for 24 h (Part A). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked solid lines the clinical Part B: Dose Cohort 1
For subject 3003, there were two reservoir
For the next part exenatide, PK was investigated when subjects received progressively higher infusion rates. Individual concentration–time profiles for subject 3003 and subject 3004 following a 7-day escalating infusion (7.5 lg/day on Day 1, 16.5 lg/day on Day 2, 25.5 lg/day on Day 3, 33 lg/day on Day 4, 42 lg/day on Day 5, 51 lg/day on Day 6, and 58.5 lg/day on Day 7) are displayed in Fig. 2. The dose-escalation paradigm resulted in daily increases in plasma concentrations in both subjects. On Day 1, the exposure had a high peak with an averaged mean (%CV) Cmax0–24h of 106 (18) pg/mL that was consistent between the two subjects. The exposure reached a Cmax of 168 pg/mL on Day 6 for subjects 3003 and 145 pg/mL on Day 7 for subject 3004. The averaged
mean
(%CV)
exenatide observations for subjects 3001 and 3002 as shown in the legend. Blue vertical dashed line shows where pump suspension occurred for subject 3001 (there was no pump suspension event recorded for subject 3002). HRS hours
Cmax0–168h
156.5 (16) pg/mL, almost identical model-predicted value of 150 pg/mL.
to
replacements on Days 3 and 6, each lasting for approximately 20 min. In addition, on the night of Day 6, the infusion was interrupted for several hours (the exact number of hours was not recorded) due to the detachment of the infusion set. Reservoir replacements occurred on the same days for subject 3004 and with a similar duration. A detailed representation of the areas where the pump was suspended can be found in Fig. 2. Table S3 in the ESM provides a detailed summary of the PK parameters for each subject. Part B: Dose Cohort 2 The manufacturer of the insulin infusion system used in this study recommends
was
replacement of the insulin reservoir and delivery system every 3 days. To differentiate
the
the effect on the PK of exenatide following reservoir replacement and catheter changes
656
Adv Ther (2015) 32:650–661
Fig. 2 Exenatide plasma concentration–time profiles after a 7-day continuous infusion where infusion rates were escalated on the morning of each day (Part B Dose Cohort 1). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the
mean. Symbol-marked solid lines the observed exenatide concentrations for subjects 3003 and 3004, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (blue for subject 3003 and red for subject 3004). HRS hours
from those due to changes in the infusion rates, a 7-day constant-rate infusion paradigm was
A constant-rate infusion of exenatide resulted in a gradual increase in plasma
used in this dose cohort. Individual concentration–time profiles for subjects 3005
concentrations followed by a steady-state phase that was maintained until the end of
and 3006 following a 7-day constant-rate
the infusion. The observed Cmax0–168h values
infusion of 25.5 lg/day are displayed in Fig. 3.
were 220 and 162 pg/mL, and the Cavg0–168h
Fig. 3 Exenatide plasma concentration–time profiles after a 7-day continuous constant infusion with a fixed rate (Part B Dose Cohort 2). Solid line the model-predicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked solid lines the
clinical exenatide observations for subjects 3005 and 3006, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (blue for subject 3005 and red for subject 3006). HRS hours
Adv Ther (2015) 32:650–661
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values were 143.3 and 113.7 pg/mL for subjects
58.5 lg/day to target exenatide exposures near
3005 and 3006, respectively. For subject 3006,
300 pg/mL.
there was a significant drop in plasma concentration in the afternoon of Day 2 (at
The individual concentration–time profiles for subjects 3007, 3008, 3009, and 3010
approximately 28 h) which only recovered after the scheduled reservoir replacement on Day 3.
following constant
In addition to this, there were two planned
together with the suspensions intervals of the
suspensions for reservoir replacements that occurred on Days 3 and 6 in both subjects.
insulin infusion pumps, are shown in Fig. 4. A constant infusion of exenatide during the first
There were a few additional interruptions when the subjects took a shower or for changes in the
48 h resulted in an averaged mean (%CV) Cavg0–48h of 119 (26) pg/mL. The infusion rate
infusion sets which are all depicted in Fig. 3.
was increased on the morning of Day 3 (at
The constant infusion of exenatide for 7 days resulted in Cavg0–168h and AUC0–168h values that
approximately 49 h) and remained constant until the end of the infusion. Post-Day 3, the
were similar for subjects 3005 and 3006. The averaged mean (%CV) Cavg0–168h was
averaged mean (%CV) Cavg48–168h was 343 (71) pg/mL. There were some fluctuations
128.5 (21) pg/mL, and this was similar to the
around the steady state in the form of high
model-predicted value of 150 pg/mL. Despite the drop in the exposure of subject 3006, there
peaks. More specifically, subject 3010 reached a transient peak exposure towards the end of the
were only minor fluctuations around the steady-state concentrations. Overall, the
infusion of approximately 700 pg/mL, which, interestingly, occurred followed the change in
reduced number of infusion rate changes seemed to result in a more stable PK profile
infusion sets. Subject 3010 presented a similar magnitude of exposure, but this was more
that followed the model’s predictions from Day
prolonged;
3 to the end of the study. Table S4 in the ESM provides a detailed summary of the PK
remains unclear. Suspensions of the infusions occurred on Days 3 and 6 in all four subjects
information for each subject.
that lasted for approximately 20 min (at approximately 54 and 126 h). In addition to
Part B: Dose Cohort 3
these, there were a few times when the infusion
In the last part of the study, a mixed constant
was interrupted, as demonstrated in Fig. 4. The constant-rate infusion of 25.5 lg/day
and escalating regimen was used to investigate further the PK variability at higher infusion
exenatide during the first two days resulted in an averaged mean (%CV) Cavg0–48h of
rates that were predicted to achieve concentrations comparable to the mean
119 (26) pg/mL that was close to the model’s
a 7-day infusion
the
mixed escalating and of 25.5–58.5 lg/day,
reason
for
this
duration
approved steady-state concentration reported
predicted value of 150 pg/mL. The Cavg0–48h in this part was also similar to the Cavg0–168h from
for Bydureon (300 pg/mL). A secondary aim was to test an infusion-modification algorithm,
Part B Dose Cohort 2 (119 vs. 128.5 pg/mL, respectively) which used the same constant
should a subject develop nausea and/or vomiting. The infusion rate was kept at
infusion rate over 7 days. The averaged mean
25.5 lg/day for the first 2 days, and in the
concentration from Day 3 until the end of the infusion Cavg48–168h was approximately
morning
343 (71) pg/mL. This is in good agreement
of
Day
3
it
was
increased
to
Adv Ther (2015) 32:650–661
658
Fig. 4 Exenatide plasma concentration–time profiles after a 7-day continuous constant infusion with mixed escalating and fixed rate (Part B Dose Cohort 3). Solid line the modelpredicted mean concentration for exenatide; upper/lower dashed lines the 95% CI around the mean. Symbol-marked
solid lines the clinical exenatide observations for subjects 3007–3010, as shown in the legend. Vertical dashed lines show where pump suspensions occurred (dark blue for subject 3007, red for subject 3008, light blue for subject 3009, and yellow for subject 3010). HRS hours
with the model’s predicted value of 300 pg/mL. Subjects 3007 and 3010 had the highest overall
subject had a mild AE of nausea and another had a mild event of decreased appetite.
54,456 pg h/mL,
There were no meaningful changes with
respectively, due to a transient high concentration peak towards the end of the
therapy in hematological, chemistry, or urinalysis parameters. Consistent with known
infusion. It was noticeable that the PK profile was very stable during the first two days for all
effects of exenatide [14, 15], values for blood pressure most often decreased with therapy and
four subjects compared to the first two days in
values for heart rate most often increased with
Part B Dose Cohort 2 that used the same infusion rate, but no explanation was found.
treatment. However, there were no measurements meeting criteria for potential
Table S5 in the ESM provides a detailed summary of the PK information for each
clinical importance.
AUC0–168h
of
64,858
and
subject.
DISCUSSION Safety There were no AEs in Part A of the study. In Part
Peptides of potential therapeutic interest with a short half-life may require a delivery technology
B, there were three AEs; none were considered serious or led to withdrawal from the study.
or a complex formulation to provide an effective, patient-friendly dosing regimen. The
One subject in Dose Cohort 2 experienced two
opportunity to study the PK behavior of these
AEs: mild abdominal discomfort and mild decreased appetite. In Dose Cohort 3, one
peptides using simple solution formulations delivered by an insulin pump may facilitate
Adv Ther (2015) 32:650–661
659
the early understanding of safety, tolerability,
been established may lead to more consistent
and their pharmacodynamic (PD) properties.
data. Second, there were occasional periods in
The current study was designed to examine the feasibility of delivering exenatide, as an
individual subjects where exposure levels were low. We hypothesize that the method of filling
exemplar peptide, via continuous subcutaneous infusion using an insulin pump. In addition, as
the reservoir by actuation of the Byetta pen, rather than filling from a glass vial under
there are very limited concentration data in the
pressure, may have allowed bubbles to enter
literature from infusion studies, our aim was to guide the doses (infusion rates) using model-
the system to a greater degree. When we targeted the mean exposure
based predictions. Overall, the model, particularly using the final 7-day infusions,
observed with Bydureon, we were interested in evaluating the safety and tolerability of
accurately predicted the mean PK parameters
delivering a continuous infusion of exenatide,
(i.e., Cmax, Cavg, AUC), although the observed within-subject variability was considerable. The
and particularly of adjusting the infusion rate to manage gastrointestinal AEs. The exenatide
limited numbers of volunteers do not allow robust statements on the BSV, although this was
slow-release formulation (Bydureon) has a reported steady-state exposure of 300 pg/mL
captured and reported in this study.
after 6 weeks of dosing 2 mg once weekly [14].
While the overall data supported the feasibility of this study methodology, there are
In Phase III studies of Bydureon, nausea was reported as an adverse event in approximately
several observations that are important. Qualitative assessment suggested that there
10–25% of subjects [14]. In the studies by Henry and colleagues [12, 13], an implantable device
was greater than anticipated within-subject variability. Insulin pumps are designed and
delivered a slow infusion of exenatide to patients with T2DM and achieved a
regulated to provide a precise subcutaneous
concentration profile similar to that seen in
insulin infusion, and thus it may be presumed that some part of the observed exenatide
the final dose cohort of the present study at the highest infusion rate. In the high dose group of
concentration variability was unique to the formulation used. Several observations may be
that study, 20% of subjects had nausea and/or vomiting after 1 week of treatment. After
useful to consider regarding the variability.
2 weeks,
First, increased concentrations were often noted at the time of pump initiation and at
experienced nausea and 80% experienced vomiting. In contrast, in our study, we had
the time of reservoir replacements (Figs. 1, 2, 3, 4). In addition, this observation also explains
few reported gastrointestinal events and these were mild and short-lived, and they did not
the deviation of the model-predicted PK for the
require treatment or an adjustment of the
initial 24-h infusion in the first cohort as well as Part B Cohorts. The deviations noted at this
infusion rate. The proportion of subjects having gastrointestinal events in the present
time seemed to be independent of dose, suggesting that more dilute concentrations of
study was lower than might have been anticipated from the literature and could be
a peptide could reduce PK variability. In
due to enrolling, by chance, subjects with less
addition, the practice of changing catheters and ceasing infusions for activities such as
sensitivity to nausea or, alternatively, to differences in sensitivity between healthy
showers during times where steady state has
subjects and patients with T2DM. It is also
approximately
40%
of
subjects
Adv Ther (2015) 32:650–661
660
possible that there may be something unique to the pump infusion paradigm we employed that
whole, and have given final approval for the version to be published.
led to the differences in the tolerability profile. Conflict of interest. Georgios Vlasakakis was an employee of GlaxoSmithKline at the time of
CONCLUSIONS We
have
demonstrated
this the
feasibility
of
utilizing insulin pumps to provide continuous subcutaneous infusion of a peptide, as well as the utility of model predictions to make dose recommendations in the early clinical development of novel peptides. This type of a study can be used as a proof-of-principle to investigate novel peptides in humans which are less
well
characterized
than
exenatide.
publication
and
has/had
stock/stock
options in the company. Susan L. Johnson was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Jiang Lin was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Xiaozhou Yao was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock
Sustained delivery using an infusion pump allows control and flexibility when
options in Gruenloh
the company. Christopher J. was an employee of
investigating PK/PD, while ensuring subject safety because of the ability to modify the
GlaxoSmithKline
at
the
time
of
this
infusion regimen. However, there are some
publication and has/had stock/stock options in the company. John P. Chism was an employee
notable limitations, particularly the observed within-subject variability, which should be
of GlaxoSmithKline at the time of this publication and has/had stock/stock options in
considered when designing a study for a novel peptide and interpreting the resulting study
the company. Derek J. Nunez was an employee
data.
of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company.
ACKNOWLEDGMENTS
Compliance
with ethics guidelines. The
study protocol and one amendment, the
This study (ClinicalTrials.gov number, NCT01857895) and the article processing
informed consent, and other relevant information were reviewed and approved by a
charges associated with this publication have
GlaxoSmithKline protocol review group and an institutional review board (Aspireirb, 11491
been sponsored by GlaxoSmithKline. We thank the investigator and subjects who participated
Woodside
Ave,
Santee,
CA
92071),
in
in the study and Rebecca Hodge, Ella Kersey, Malcolm Young, and Steve Stagliano
accordance with the International Conference on Harmonization Good Clinical Practice
(Medtronic Inc.) for their valuable input. All
guidelines and the principles of the Declaration of Helsinki. Written informed
named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a
consent was obtained from each subject prior to the performance of any study-specific procedures.
Adv Ther (2015) 32:650–661
661
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