432934

JCPXXX10.1177/0091270011432934Yin et

alThe Journal of Clinical Pharmacology / Vol XX No XX (20XX)

2012

Pharmacokinetics and Pharmacodynamics

of Figitumumab, a Monoclonal Antibody
Targeting the Insulin-Like Growth Factor 1
Receptor, in Healthy Participants

The Journal of Clinical Pharmacology

53(1) 2128
The Author(s) 2012
DOI: 10.1177/0091270011432934

Donghua Yin, PhD1, Barbara Sleight, MD1, Christine Alvey, MS2,

Arne G. Hansson, MD3, and Akintunde Bello, PhD4

Abstract
This study determined the pharmacokinetics (PK) of figitumumab and its effects on insulin-like growth factor (IGF) axis-related biomarkers,
following a single intravenous dose (10 [n = 16] and 20 [n = 12] mg/kg) in healthy adults. Serial blood sampling for PK and biomarkers was
conducted up to 84 days postdose. A dose increase from 10 to 20 mg/kg led to 1.9- and 2.4-fold increases in mean Cmax and AUC , respectively.
Median disposition half-life was 21.1 and 27.8 days at 10 and 20 mg/kg, respectively. At 10 and 20 mg/kg, figitumumab increased total IGF-1, free
IGF-1, IGF binding protein (IGFBP) 3, and insulin by 4.1- and 4.8-, 8.3- and 12.1-, 2.4- and 2.9-, and 7.3- and 9.8-fold, respectively; increases were
sustained throughout the 84-day period. There was a slight and transient elevation in IGF-2. Mean plasma glucose increased by 18% and 16%
at 10 and 20 mg/kg, respectively. Most treatment-related adverse events were mild in severity; the most common included dry eye (n = 9) and
ocular hyperemia (n = 9) in the 20-mg/kg group. No antidrug antibodies were detected. Overall, figitumumab (10 or 20 mg/kg) demonstrated
PK properties typical of IgG2 antibodies and produced substantial and sustained increases in IGF-1 (total and free), IGFBP-3, and insulin.

Keywords
figitumumab, IGF-1 receptor, pharmacokinetics , pharmacodynamics

The insulin-like growth factor 1 receptor (IGF-1R) is a

transmembrane tyrosine kinase receptor that mediates the
principal biological actions of its endogenous ligands,
IGF-1 and IGF-2, in human growth and development.1-3
Upon ligand binding, IGF-1R undergoes autophosphorylation and subsequently triggers intracellular signaling
through the phosphatidylinositol 3-kinase (PI3K)/AKT
or the mitogen-activated protein kinase (MAPK) pathways.4,5 IGF-1R signaling initiated by IGFs regulate the
growth, proliferation, differentiation, and survival of normal cells.5,6 However, altered IGF-1R signaling at the
ligand or receptor level has been reported in a variety of
disorders, including cancer, diabetes, and neurodegenerative, cardiovascular, and rheumatic diseases.2,3,5,7-9
Figitumumab (CP-751,871) is a fully human, IgG2
monoclonal antibody that specifically targets the IGF-1R.
Preclinical studies demonstrated that figitumumab inhibits IGF-1R autophosphorylation initiated by IGF-1 or
IGF-2 and induces receptor downregulation.10 As the first
IGF-1R-targeting monoclonal antibody to enter clinical
trials, figitumumab has been under investigation as
a therapy for a variety of cancers, including lung,
breast, and Ewing sarcoma. Early clinical trials showed
that figitumumab was well tolerated in cancer patients
after repeated administration every 3 or 4 weeks at
doses up to 20 mg/kg.11-13 The most common adverse
events (AEs) related to figitumumab treatment included

hyperglycemia, anorexia, nausea, elevated liver function

enzymes, diarrhea, hyperuricemia, and fatigue.11-14 Early
trials also showed that figitumumab exhibited preliminary anticancer activity as a single agent in Ewing sarcoma and enhanced the response rate and progression-free
survival benefit of paclitaxel and carboplatin in non
small cell lung cancer (NSCLC).14,15 However, 2 randomized phase III trials of figitumumab in NSCLC were
recently discontinued because of unfavorable overall survival outcome. Safety data from one of the trials also
indicated an imbalance in the number of deaths and serious AEs such as asthenia and hyperglycemia in the figitumumab arm.16 Biomarker analyses have identified patient
subpopulations that may preferentially benefit from figitumumab treatment.17,18

Oncology Business Unit, Pfizer, Inc, Groton, CT, USA

Primary Care Business Unit, Pfizer, Inc, Groton, CT, USA
3
New Haven Clinical Research Unit, Pfizer, Inc, New Haven, CT, USA
4
Oncology Business Unit, Pfizer, Inc, New York, NY, USA
2

Submitted for publication 27-May-2011; accepted 06-Nov-2011

Corresponding Author:
Donghua Yin, Clinical Pharmacology, Oncology Business Unit, Pfizer,
Inc, 445 Eastern Point Rd, MS 8260-2139, New London, CT 06340,
USA
Email: [email protected]

22
In studies of cancer patients, the pharmacokinetics
(PK) of figitumumab and changes in IGF-1-associated
biomarkers have been evaluated following repeated dosing. However, because of the relatively long half-life (t1/2)
of figitumumab at doses 10 mg/kg, the PK of the terminal disposition phase has not been well characterized
even with plasma concentration data collected over a dosing interval of 3 to 4 weeks. The present study was
designed to evaluate the PK, biomarker responses, and
safety of figitumumab in healthy adults for an extended
duration after administration of single intravenous doses
of 10 and 20 mg/kg.

Methods
Study Design. This was a phase I, single-dose, openlabel study conducted at a Pfizer Clinical Research Unit
(CRU). Healthy male and female (of nonchildbearing
potential) participants aged between 18 and 55 years,
with a body mass index of 17.5 to 30.5 kg/m2 and a total
body weight >50 kg, were considered for enrollment.
Major exclusion criteria included evidence or history of
clinically significant disease, laboratory or physical
examination abnormalities, use of prescription or nonprescription drugs and dietary supplements, and positive serological test for hepatitis B surface antigen, antihepatitis
C antibody, or human immunodeficiency virus. All participants underwent screening within 28 days before the
start of treatment on day 1. Eligible participants were
assigned to 1 of 2 figitumumab dosing cohorts: 10 and
20 mg/kg; the 20-mg/kg cohort did not receive study
treatment until all of the 10-mg/kg cohort participants
had been observed for at least 1 week after figitumumab
administration. On day 1, participants received a single
dose of figitumumab via a 1-hour intravenous infusion.
They were discharged from the CRU on day 2 and thereafter returned for completion of necessary planned procedures at prespecified dates until day 85. During the study
period, participants were required to abstain from concomitant medications and from strenuous exercise for at
least 48 hours prior to blood sample collection.
The study was conducted in compliance with the ethical principles originating in or derived from the
Declaration of Helsinki, all International Conference on
Harmonization (ICH) Good Clinical Practice (GCP)
Guidelines, and the Food and Drug Administration (FDA)
Regulations (Title 21 Code of Federal Regulations [21
CFR], Parts 50, 56, and 312). The study protocol was also
approved by the IntegReview Ethical Review Board.
Written informed consent was obtained prior to the participant entering the study (before initiation of protocolspecified procedures). Study participants were financially
compensated.

The Journal of Clinical Pharmacology / Vol 53 No 1 (2013)

Pharmacokinetic Assessment. Serial blood samples for

determination of figitumumab concentration were collected from all participants immediately before figitumumab infusion and at 1 hour, 24 hours, and 7, 14, 21,
28, 42, 56, 70, and 84 days after the end of infusion. All
efforts were made to obtain the PK samples within 10%
of the scheduled time through day 29 and within 3 days of
the scheduled time for later time points. Blood samples
were immediately centrifuged at ~1700 for about
10 minutes at 4C. Plasma fractions were obtained and
stored at 70C 10C until analysis.
Plasma concentrations of figitumumab were analyzed
by ALTA Analytical Laboratory (San Diego, California)
using a validated enzyme-linked immunosorbent assay
(ELISA).10 The lower limit of quantitation (LLOQ) for
the assay was 120 ng/mL. The assay accuracy, expressed
as interassay percent relative error (%RE) for quality
control (QC) concentrations, ranged from 0.3% to 3.7%.
The assay precision, expressed as interassay percent coefficient of variation (%CV) of the mean estimated concentrations of QC samples, was 7% to 13%.
The plasma concentration-time data were analyzed by
noncompartmental methods using eNCA (version 2.2.1), a
21 CFR Part 11compliant system developed by Pfizer, Inc
for PK noncompartmental analysis. The maximum concentration (Cmax) was obtained directly from individual
concentration-time data. The terminal t1/2 was estimated as
ln2/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentrationtime curve. Area under the plasma concentration-time
curve (AUC) from time 0 to the time of the last quantifiable concentration (AUClast), as well as from time 0 to 504
hours (21 days) after dosing (AUC504), was determined
using the linear-log trapezoidal method. AUC from time 0
to infinite time (AUC) was calculated as AUClast + Clast/
kel, where Clast was the last quantifiable concentration.
Plasma clearance (CL) was calculated as Dose/AUC, and
the volume of distribution based on the elimination phase
(Vz) was calculated as CL/kel.
Assessment of Biomarker Responses. Serial blood samples
for determination of concentrations of IGF-1 (total and
free), IGF-2, IGF binding protein (IGFBP)3, insulin, and
glucose were collected from all participants immediately
before figitumumab infusion and at 1 hour, 24 hours, and
7, 14, 21, 28, 42, 56, 70, and 84 days after the end of infusion. The biomarker samples were collected after at least 4
hours of fasting. Blood samples were collected into serum
separator tubes and allowed to clot for approximately 30
minutes. The tubes were then centrifuged at ~2850 for 10
minutes to obtain serum samples. The samples for IGF-1
(total and free), IGF-2, and IGFBP-3 were stored at 80C
until assay. The samples for insulin and glucose were analyzed immediately after collection.

23

Yin et al
Measurement of Total and Free IGF-1 Concentrations.
Serum total and free IGF-1 concentrations were determined at Advion BioServices, Inc (Manassas, Virginia)
using validated ELISA assays. For measurement of total
IGF-1, the samples were pretreated to release IGF-1 from
binding proteins. Untreated samples were used for quantitation of free IGF-1. The human IGF-1 Quantikine
ELISA kit (R&D Systems, Minneapolis, Minnesota) was
used. Briefly, serum samples were added to a microtiter
plate precoated with a mouse monoclonal antibody specific for IGF-1. A horseradish peroxidase (HRP)conjugated polyclonal anti-IGF-1 antibody was then added to
the plate. After incubation and washing, a chromogenic
HRP substrate was used for color development, and the
optical density was measured using a microplate reader to
determine the amount of bound IGF-1. The LLOQ was
0.150 ng/mL for total and free IGF-1. The interassay
accuracy (%RE) of the QC samples ranged from 1.5%
to 1.1% for total IGF-1 and 5.1% to 2.1% for free IGF-1.
The interassay precision (%CV) of the QC samples was
2.3% for both free and total IGF-1.
Measurement of IGF-2 Concentrations. Serum IGF-2
was assayed at Advion BioServices using a validated
ELISA assay, which used the Beckman Coulter (Brea,
California) Active IGF-2 ELISA kit, including a mouse
monoclonal capture antibody against human IGF-2 and
an HRP-conjugated polyclonal antihuman IGF-2 as the
detection antibody. Briefly, serum samples were first
incubated with the capture antibody in a microtiter plate,
and the detection antibody conjugate was then added.
After adding the HRP substrate, the absorbance was measured using a microplate reader to determine the amount
of bound IGF-2. The LLOQ was 150 ng/mL. The interassay accuracy (%RE) of the QC samples ranged from
3.3% to 0.2%. The interassay precision (%CV) of the
QC samples was 12.2%.
Measurement of IGFBP-3 Concentrations. Serum samples were analyzed for IGFBP-3 concentrations at Advion
BioServices, Inc using a validated solid-phase sandwich
ELISA spectrophotometric assay. The assay used the
Quantikine IGFBP-3 kit from R&D Systems. Serum
samples were added to a plate precoated with a mouse
monoclonal antibody against human IGFBP-3. An HRPconjugated polyclonal antihuman IGFBP-3 antibody was
then added to the plate. After incubation and washing, the
HRP substrate was added and the absorbance was measured using a microplate reader to determine the bound
IGFBP-3. The LLOQ was 2.0 ng/mL. The interassay
accuracy (%RE) of the QC samples ranged from 0.4% to
4.1%. The interassay precision (%CV) of the QC samples
was 4.7%.
Measurement of Insulin and Glucose Concentrations.
Serum concentrations of insulin and glucose were analyzed in real time in the laboratory of New Haven Clinical Research Unit, Pfizer, Inc (New Haven, Connecticut).
Glucose was measured by a glucose oxidase method with

the Virtos 950 (Ortho-Clinical Diagnostics, Raritan, New

Jersey). The intra-assay and interassay %CV for glucose
was 0.7% and 1.3%, respectively. The detection limit
was 20 mg/dL. Insulin was measured using a solid-phase,
competitive chemiluminescent enzyme assay with the
Immulite 1000 automated analyzer (Siemens, New York,
New York). The intra-assay and interassay %CV for insulin was 6.4% and 8.0%, respectively.
Safety Assessments. At each study visit, participants
were evaluated for safety via laboratory tests, monitoring
of vital signs (supine pulse rate and blood pressure), and
AE assessments. Doppler echocardiography was also
performed at screening and 28 and 84 days after figitumumab infusion.
Immunogenicity Assessment. Serum samples for the
detection of total and neutralizing antidrug antibodies
(ADAs) were collected immediately before figitumumab
infusion and at 14, 28, 56, and 84 days after infusion.
Detection of antifigitumumab antibodies was conducted
by PPD, Inc (Richmond, Virginia) using a validated
electrochemiluminescent (ECL) immunoassay. Serum
samples were first incubated with biotinylated-figitumumab (B-figitumumab) and ruthenylated-figitumumab
(Tag-figitumumab) to allow formation of an antibody
complex between the ADA and the labeled forms of figitumumab. The samples were then added to a Meso-Scale
Discoverystreptavidin (MSD-SA) plate (Meso-Scale
Discovery, Gaithersburg, Maryland), where the antibody
complex would bind to the streptavidin coat via B-figitumumab. The chemiluminescence from the Tag-figitumumab of the antibody complex was measured using the
MSD Sector PR 100 plate reader to obtain the end point
titer of the ADA. The relative assay sensitivity was
11.1 ng/mL.
Statistical Analysis. Figitumumab PK parameters and
biomarker concentration-time data were summarized
descriptively by dose. Adverse events and safety laboratory data were summarized by dose.

Results
Study Participants. In total, 28 healthy male participants
were enrolled to receive figitumumab at 10 and 20 mg/kg.
All participants completed the planned procedures during
the 84-day study period and were included in the data
analysis. As shown in Table 1, demographic characteristics were similar between the treatment groups.
Pharmacokinetics of Figitumumab. After a single intravenous infusion at doses of 10 and 20 mg/kg, figitumumab
concentrations decreased in a multiexponential manner
(Figure 1). For both the 10- and 20-mg/kg dose levels,
there was a relatively rapid decline in figitumumab plasma
concentrations during the initial phase of up to 7 days,
followed by a slower decline thereafter. At 10 mg/kg, the
rate of decrease in concentrations increased again after
approximately 70 days postdose. An evaluation of

24

The Journal of Clinical Pharmacology / Vol 53 No 1 (2013)

Table 1. Demographic Characteristics of Enrolled Participants

Figitumumab,
10 mg/kg
No. of participants
Gender, No.
Male
Female
Age, y
18-44, No.
45-64, No.
Mean
SD
Race, No.
White
Black
Asian
Other
Body mass index, kg/m2
Mean
SD

Figitumumab,
20 mg/kg

Total

16

12

28

16
0

12
0

28
0

16
0
31
6

11
1
30
8

27
1
31
7

4
10
0
2

3
8
1
0

7
18
1
2

25.7
2.6

25.1
2.4

25.4
2.5

Figure 1. Mean ( SD) plasma concentration-time profiles of

figitumumab after a single intravenous dose to healthy adults.

individual PK profiles at the 10-mg/kg dose indicated

that the decline in concentration accelerated sharply once
the concentrations approached approximately 10 mg/L in
a few participants (data not shown).
Figitumumab showed a dose-dependent PK at the
dose levels tested. As shown in Table 2, when the dose
increased from 10 to 20 mg/kg, mean Cmax appeared to
increase proportionally (by 1.9-fold), but the increase in
mean AUC (2.4-fold) appeared to be greater than doseproportional. The increase in dose was also associated
with a 16% decrease in mean plasma CL and a prolongation of mean t1/2.
Effects of Figitumumab on Biomarkers. At 10 and 20 mg/kg,
figitumumab was associated with a substantial, protracted, and dose-dependent increase in total and free

IGF-1 (Table 3; Figure 2a,b). Concentrations of both biomarkers increased from baseline values within 24 hours
after dosing and remained at markedly elevated levels up
to 84 days postdose (the last measurement time point).
The maximum increases in mean total IGF-1 from corresponding baseline levels were 4.1- and 4.8-fold at the 10and 20-mg/kg doses, respectively. The time courses for
changes in free IGF-1 levels largely paralleled those for
total IGF-1. The greater magnitude of change seen for
free IGF-1 concentrations compared with total IGF-1
suggests that figitumumab had the primary effect of
increasing the free fraction of IGF-1.
Figitumumab treatment was also associated with a
rapid elevation in serum IGF-2 concentrations; however,
this effect appeared to be relatively small and was transient (Table 3; Figure 2c). Although there was no apparent dose response in the increase of IGF-2 with
figitumumab administration over the 10 to 20 mg/kg dose
range, the large intersubject and intrasubject variability in
IGF-2 concentrations did not permit a definitive
conclusion.
A dose-dependent increase in IGFBP-3 concentrations
was observed following figitumumab administration at
the 2 dose levels (Table 3; Figure 2d). The time courses
for changes in IGFBP-3 levels appeared similar to those
for total and free IGF-1, with marked elevations in
IGFBP-3 concentrations noted between approximately 7
and 84 days postdose. However, the magnitude of change
in IGFBP-3 concentrations was somewhat lower than that
seen for free and for total IGF-1.
Single doses of figitumumab also resulted in sustained
elevations in fasting serum insulin and glucose concentrations (Table 3; Figure 2e,f). The apparent stimulatory
effect of figitumumab on insulin was rapid, with an
increase in concentrations observable as early as 1 hour
after dosing. Interestingly, there appeared to be a small
drop in serum glucose concentrations within 24 hours
after figitumumab dosing; however, by 7 days postdose,
glucose levels were higher than at baseline. The magnitude of increase in glucose levels was markedly lower
than that seen for insulin. The lack of an apparent dose
response for glucose concentrations over a figitumumab
dose range of 10 to 20 mg/kg (ie, a similar magnitude of
effect) suggests that the maximum effect was achieved at
the lower dose of 10 mg/kg.
Safety. No deaths or other serious AEs were reported in
this study. In addition, no permanent or temporary discontinuations due to AEs occurred. All causality AEs
were experienced by 9 of 16 participants at 10 mg/kg
(33 events) and by all 12 participants at 20 mg/kg (60
events). Twenty-three AEs at 10 mg/kg and 50 AEs at 20
mg/kg were considered related to study treatment. The
most frequently occurring AEs were dry eye (9 participants) and ocular hyperemia (9 participants), which were

25

Yin et al
Table 2. Pharmacokinetic Parameters of Figitumumab After a Single Intravenous Administration
Figitumumab, 10 mg/kg
Parameter

No.

Cmax, mg/L
AUC504, mgh/L
AUClast, mgh/L
AUC, mgh/L
CL, mL/d/kg
Vz, mL/kg
t1/2, d

16
16
16
13
13
13
13

Figitumumab, 20 mg/kg

Mean SD
225 54
46 020 8009
80 740 14 184
87 110 12 981
2.81 0.38
84.9 13.7
21.1 3.0

No.

Mean SD

12
12
12
12
12
12
12

421 62
94 830 14 502
184 000 27 811
209 800 33 809
2.35 0.44
92.2 15.0
27.8 5.8

Abbreviations: AUC504, area under the plasma concentration-time curve (AUC) from time 0 to 504 hours (21 days) after dosing; AUClast, AUC from time 0
to the time of the last quantifiable concentration; AUC, AUC from time 0 to infinite time; CL, plasma clearance; Cmax, maximum plasma concentration; t1/2,
terminal half-life;Vz, volume of distribution based on the elimination phase.

Table 3. Biomarker Responses Following a Single Intravenous Administration of Figitumumab in Healthy Participants
Figitumumab, 10 mg/kg (n = 16)
Biomarker
Total IGF-1, ng/mL
Free IGF-1, ng/mL
IGF-2, ng/mL
IGFBP-3, ng/mL
Insulin, mIU/mL
Glucose, mg/dL

Figitumumab, 20 mg/kg (n = 12)

Baseline

Cmax

tmax, d

Maximum Fold
Increase

Baseline

Cmax

tmax, d

Maximum Fold
Increase

138 33
17 7
1550 440
2041 546
5.1 3.2
88 6

566 142
143 45
2039 582
4945 1035
37.6 23.8
104 21

56
56
14
56
42
42

4.1
8.3
1.3
2.4
7.3
1.2

128 23
14 6
1476 229
1978 496
4.1 3.3
87 5

610 143
168 43
1909 275
5819 1310
40.0 34.5
101 16

84
56
21
56
56
56

4.8
12.1
1.3
2.9
9.8
1.2

Abbreviations: Baseline, the mean SD concentration at predose on study day 1; Cmax, the mean SD concentration observed at the time of maximal
change from baseline; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; maximum fold increase, ratio of mean Cmax to the
mean baseline concentration; tmax, the time in days postdose when the maximum change in the mean concentration (in relation to the baseline) occurred.

experienced only by those in the 20-mg/kg group; all participants in that treatment group experienced eye disorder
AEs. Other frequently occurring AEs included headache
(6 participants), fatigue (4 participants), tinnitus (3 participants), diarrhea (3 participants), nausea (3 participants), and somnolence (3 participants). All of the
preceding frequently occurring AEs were considered
treatment related, with the exception of 1 AE of headache. Of the treatment-related AEs, there was 1 severe
AE of fatigue that lasted for 8 days in 1 participant and 1
moderately severe headache that lasted 24 hours in
another participant (both from the 20-mg/kg group); all
other treatment-related AEs were mild in severity.
It was originally planned that the study would enroll
an additional cohort of participants who were to receive
2 doses of figitumumab 20 mg/kg on each of 2 consecutive days. However, the study was terminated early
because of mild-severity AEs of eye disorders and tinnitus. All eye disorder AEs had resolved by the end of the
study, with the exception of the mild-severity AE of dry
eye in 1 participant. The AEs of tinnitus resolved in 2
participants within 21 and 171 days, respectively, from
the start of symptoms; in the third participant, tinnitus
resolved within 25 days in one ear but was ongoing in the

other ear 227 days after dosing. Two of the 3 participants

with tinnitus also had an abnormal audiogram of mild
severity.
There were no AEs relating to laboratory test results.
The most common laboratory test abnormality was low
reticulocyte count, which was observed in 5 of 16 participants in the 10-mg/kg group and in 6 of 12 participants in
the 20-mg/kg group. The incidence of laboratory test
abnormalities without regard to baseline abnormality was
similar between the treatment groups.
Immunogenicity. Following single 10- and 20-mg/kg
doses of figitumumab, 109 postdose ADA samples were
collected from 28 participants for up to 84 days postdose.
None of the samples was positive for ADA in the screening assay.

Discussion
In clinical studies, repeated doses of figitumumab have
been administered to cancer patients every 3 or 4 weeks
over the dose range of 0.025 to 30 mg/kg. Results from
these studies indicate that figitumumab PK are dose
dependent, probably due to the involvement of saturable
target-mediated disposition.11,12,14,15,19 Because of the rela-

26

The Journal of Clinical Pharmacology / Vol 53 No 1 (2013)

Figure 2. Mean ( SD) serum concentration-time profiles of (a) total IGF1, (b) free IGF1, (c) IGF2, (d) IGFBP3, (e) insulin, and (f) glucose after a
single intravenous dose to healthy adults. All concentrations are expressed as percentages of the pretreatment baseline. Curves represent the mean
data and error bars indicate the SD. IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein.

tively long t1/2 of figitumumab at dose levels 10 mg/kg,

PK sampling within the 3- to 4-week dosing interval in
cancer patients has not allowed full characterization of
the terminal disposition phase in most individuals at
therapeutic dose levels. The present study permitted
extensive PK sampling over an extended duration to
allow adequate characterization of the single-dose figitumumab PK profiles at doses 10 mg/kg.

The PK profiles of figitumumab following an intravenous infusion were characterized by a multiexponential

decline in plasma concentration, which is typical of therapeutic antibodies with target-mediated disposition. As
observed in a few participants in the 10-mg/kg cohort,
there was an accelerated decline in concentrations when
they reached approximately 10 mg/L, suggesting that
this is a maximum threshold concentration at which

Yin et al
IGF-1 receptors are able to remove figitumumab from
circulation. This observation is also consistent with
the very rapid decline in figitumumab plasma concentrations seen previously in cancer patients at dose levels
0.8 mg/kg.11,15
Results from the present study suggest that singledose figitumumab PK in healthy participants were similar
to those observed in cancer patients. The mean Cmax and
AUC504 values in healthy participants were similar to
those observed in cancer patients at the same dose levels.12,14,15,19 However, there appeared to be less intersubject variability associated with Cmax and AUC504 in
healthy participants, where the CV% of Cmax and AUC504
ranged from ~15% to 24%; conversely, in cancer patient
trials, the CV% of these parameters ranged from ~19% to
46%.12,15 In the present study, the t1/2 of figitumumab was
determined to be approximately 21.1 to 27.8 days. The
observed t1/2 values are consistent with the observation of
approximately 2-fold accumulation in steady-state exposure following repeated administration of figitumumab at
10 or 20 mg/kg every 3 or 4 weeks to cancer patients.15,19
Pharmacokinetic results from this study support the figitumumab dosing schedule of once every 3 to 4 weeks in
cancer therapy.
Figitumumab has been associated with an increase in
levels of circulating IGF-1 (total and free), IGFBP-3, insulin, and glucose in previous studies in cancer patients.12,15,19
Notably, hyperglycemia has been identified as one of the
most common AEs in figitumumab cancer patient trials.11,12,14,15,19 Results from the present study confirm the
stimulatory effects of figitumumab on these biomarkers. In
addition, this study showed that IGF-2 levels were only
modestly increased with figitumumab treatment. While the
design of previous figitumumab cancer patient trials
allowed only limited sampling of these biomarkers, the
present study permitted a more extensive characterization
of the biomarker time courses following figitumumab dosing. These analyses showed that there was a time delay
between figitumumab PK and the ensuing responses of the
biomarkers; maximal responses for these biomarkers were
not achieved until at least 2 weeks after the time of maximal figitumumab concentration.
There are at least 2 potential mechanisms by which
blockade of the IGF-1 receptor by figitumumab could
lead to increases in circulating IGF-1. First, figitumumab
could inhibit the elimination of circulating IGF-1 through
downregulation of IGF-1 receptors, as receptor-mediated
endocytosis is postulated to be a major clearance mechanism for IGF-1.20 Second, blockade of IGF-1 receptors in
the pituitary gland could potentially remove the negative
feedback of the growth hormoneIGF-1 axis by IGF-1,
leading to increased release of growth hormone and subsequent production of IGF-1 by the liver. The latter
mechanism is supported by the observation that

27
figitumumab increases serum growth hormone concentrations in cancer patients.12
Treatment with figitumumab led to a greater increase
in free IGF-1 than in total IGF-1. The elevation in the
IGF-1 free fraction (ie, the ratio of the free concentration
to the total concentration) suggests that the relatively
modest increase in IGFBP-3, the predominant binding
protein of circulating IGF-1, was not sufficient to fully
compensate for the change in IGF-1 and maintain the
equilibrium between the free and bound forms of IGF-1.
The effect of figitumumab on IGFBP-3 could be secondary to the changes in other biomarkers, as the production
of IGFBP-3 is known to be regulated by growth hormone,
IGF-1, and insulin.21
The effects of figitumumab on insulin and glucose
were likely mediated through the altered growth hormoneIGF-1 axis, as opposed to through direct interactions of figitumumab with the insulin receptor. It has been
demonstrated that, at the concentrations achieved in clinical studies, the insulin receptor would not be inhibited by
figitumumab.10,18 On the other hand, effects of the growth
hormoneIGF-1 axis on insulin sensitivity and glucose
homeostasis have been well documented.22 The results
obtained in the present study demonstrate that single
doses of figitumumab at 10 and 20 mg/kg can markedly
increase insulin and moderately increase glucose.
Interestingly, the current results appear to suggest that the
effects of figitumumab on glucose may have already
reached their maxima following a single dose at 10 mg/kg.
It is important to note that the therapeutic relevance of
this finding from a relatively small group of healthy participants requires further confirmation, especially in light
of the relatively large intersubject variability in insulin
and glucose responses observed.
The treatment-related AEs observed in healthy participants after a single dose of figitumumab were mostly
mild; the AEs of headache, fatigue, diarrhea, and nausea
have been previously noted in cancer patients trials.11-15,19
It is noteworthy that the AEs of eye disorders and tinnitus
were rare (<2%) in cancer patients who received repeated
figitumumab dosing at 10 or 20 mg/kg (internal data), but
these AEs occurred with a much higher frequency in
healthy participants after just a single figitumumab dose.
Also, it does not appear that there is any dose-response
relationship for the AE of tinnitus because all 3 cases of
tinnitus were reported at 10 mg/kg but none at 20 mg/kg.
The mechanisms for figitumumab to cause tinnitus and
eye disorders are not clear, nor are the causes for the
observed difference in frequency of these AEs between
healthy individuals and cancer patients.
In summary, PK profiles of figitumumab after a single
dose at 10 and 20 mg/kg have been characterized in
healthy adults. Overall, figitumumab demonstrated PK
properties typical of IgG2 antibodies. The disposition t1/2

28
values of 21.1 days (10 mg/kg) and 27.8 days (20 mg/kg)
support the figitumumab dosing schedule of once every 3
or 4 weeks that has been used in cancer patients. The PK
characteristics in healthy adults were similar to those
observed in cancer patients. After single figitumumab
doses of 10 and 20 mg/kg, substantial and sustained
increases in serum concentrations of IGF-1 (total and
free), IGFBP-3, and insulin were noted. Treatment with
figitumumab at these doses also resulted in slight
increases in IGF-2 and glucose concentrations. No antidrug antibodies were detected for up to 84 days after
a single intravenous infusion of figitumumab at 10 and
20 mg/kg in healthy adults.
Acknowledgments
We thank the staff of the Pfizer Clinical Research Unit for conduct of the study. We also thank Matthew A. Green, Dr Antonio
Gualberto, Leilani Kapili, JoAnn LaFargue, Dr Sandra Meech,
Maryam Monajati, Grace Ni, Dr Larry K. Ritzhaupt, Rong
Wang, and other members of the Pfizer Figitumumab
Development Team for contributions to the study. Editorial support was provided by Nicola Crofts at ACUMED (Tytherington,
UK) and was funded by Pfizer, Inc.

Declaration of Conflicting Interests

All authors are employees of Pfizer, Inc and hold Pfizer stock
options.

Funding
This study was sponsored by Pfizer, Inc.

References
1. Dupont J, Holzenberger M. Biology of insulin-like growth factors
in development. . 2003;69:257-271.
2. Juul A. Serum levels of insulin-like growth factor I and its binding
proteins in health and disease. . 2003;13:113-170.
3. Cohen P. Overview of the IGF-I system. . 2006;65(suppl 1):3-8.
4. Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The
type 1 insulin-like growth factor receptor pathway. . 2008;14:63646370.
5. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. . 2008;8:915-928.
6. Romano G. The complex biology of the receptor for the insulin-like
growth factor-1. . 2003;16:525-531.
7. Denko CW, Malemud CJ. Role of the growth hormone/insulin-like
growth factor-1 paracrine axis in rheumatic diseases. . 2005;35:2434.

The Journal of Clinical Pharmacology / Vol 53 No 1 (2013)

8. Mohamed-Ali V, Pinkney J. Therapeutic potential of insulin-like
growth factor-1 in patients with diabetes mellitus. . 2002;1:399410.
9. Abbas A, Grant PJ, Kearney MT. Role of IGF-1 in glucose regulation and cardiovascular disease. . 2008;6:1135-1149.
10. Cohen BD, Baker DA, Soderstrom C, et al. Combination therapy
enhances the inhibition of tumor growth with the fully human anti
type 1 insulin-like growth factor receptor monoclonal antibody
CP-751,871. . 2005;11:2063-2073.
11. Lacy MQ, Alsina M, Fonseca R, et al. Phase I, pharmacokinetic and
pharmacodynamic study of the anti-insulinlike growth factor type 1
receptor monoclonal antibody CP-751,871 in patients with multiple
myeloma. . 2008;26:3196-3203.
12. Haluska P, Shaw HM, Batzel GN, et al. Phase I dose escalation
study of the anti insulin-like growth factor-I receptor monoclonal
antibody CP-751,871 in patients with refractory solid tumors. .
2007;13:5834-5840.
13. Molife LR, Fong PC, Paccagnella L, et al. The insulin-like growth
factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results
of a phase Ib dose-escalation, open-label study. . 2010;103:332339.
14. Olmos D, Postel-Vinay S, Molife LR, et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody
figitumumab (CP-751,871) in patients with sarcoma and Ewings
sarcoma: a phase 1 expansion cohort study. . 2010;11:129-135.
15. Karp DD, Pollak MN, Cohen RB, et al. Safety, pharmacokinetics,
and pharmacodynamics of the insulin-like growth factor type 1
receptor inhibitor figitumumab (CP-751,871) in combination with
paclitaxel and carboplatin. . 2009;4:1397-1403.
16. Jassem J, Langer CJ, Karp DD, et al. Randomized, open label,
phase III trial of figitumumab in combination with paclitaxel and
carboplatin versus paclitaxel and carboplatin in patients with nonsmall cell lung cancer (NSCLC). . 2010;28:Abstract 7500.
17. Gualberto A, Dolled-Filhart M, Gustavson M, et al. Molecular
analysis of nonsmall cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition.
. 2010;16:4654-4665.
18. Gualberto A, Hixon ML, Karp DD, et al. Pre-treatment levels of
circulating free IGF-1 identify NSCLC patients who derive clinical
benefit from figitumumab. . 2011;104:68-74.
19. Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and
pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. .
2010;65:765-773.
20. Mizuno N, Kato Y, Iwamoto M, et al. Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers. .
2001;18:1203-1209.
21. Jogie-Brahim S, Feldman D, Oh Y. Unraveling insulin-like growth
factor binding protein-3 actions in human disease. . 2009;30:417437.
22. Holt RI, Simpson HL, Snksen PH. The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis. .
2003;20:3-15.