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Absolute Bioavailability of Imatinib (Glivec®) Orally versus Intravenous Infusion

Bin Peng, Catherine Dutreix, Gunther Mehring, Michael J. Hayes, Monique Ben-Am, Michael Seiberling, Rolf Pokorny,
Renaud Capdeville and Peter Lloyd
J Clin Pharmacol 2004 44: 158
DOI: 10.1177/0091270003262101
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Absolute Bioavailability of Imatinib (Glivec®)
Orally versus Intravenous Infusion
Bin Peng, Catherine Dutreix, Gunther Mehring, Michael J. Hayes, Monique Ben-
Am, Michael Seiberling, Rolf Pokorny, Renaud Capdeville, and Peter Lloyd
The purpose of this study was to investigate the absolute
bioavailability of a single oral dose of imatinib (Glivec®),
400 mg (capsules vs. oral solution), compared with
imatinib, 100 mg (intravenous [i.v.] infusion), in healthy
subjects. Twelve subjects received a single treatment in
each treatment period: a 400-mg oral dose of imatinib in
capsule form or as a solu- tion or a 100-mg i.v. infusion of
imatinib. Plasma imatinib concentrations were measured
following each treatment; pharmacokinetic parameters and
absolute bioavailability were determined. Absolute
bioavailability values (compared with i.v. infusion) for the
imatinib capsule and oral solution
I matinib (Glivec®) is a protein-tyrosine kinase inhibi-
tor that potently inhibits the BCR-ABL, KIT, and
platelet-derived growth factor receptor tyrosine kin-
ases at the in vitro, cellular, and in vivo levels.1-5 Pro-
tein-tyrosine kinases play a fundamental role in signal
transduction, and deregulated activity of these en-
zymes has been observed in cancer and benign
proliferative disorders.6 Clinical results from Phase I
and Phase II trials with imatinib in patients suffering
from chronic myeloid leukemia (CML) with interferon
(IFN) resistance or from advanced Philadelphia
chromosome-positive leukemias showed antitumor ac-
tivity based on overall hematologic and cytogenetic re-
sponse rates with this single-agent treatment at well-
tolerated doses.7-11
The Phase III International Randomized Interferon
versus STI571 (IRIS) study was undertaken to
compare
From the Novartis Pharmaceuticals, Florham Park, New Jersey (B. Peng,
M. Hayes, M. Ben-Am); Novartis Pharma AG, Basel, Switzerland (C.
Dutreix,
G. Mehring, R. Capdeville, P. Lloyd); and Swiss Pharma Contract,
Allschwil, Switzerland (M. Seiberling, R. Pokorny). Submitted for
publica- tion July 18, 2003; revised version accepted November 26,
2003. Ad-
dress for reprints: Bin Peng, MD, PhD, Clinical Pharmacology, Novartis
Pharmaceuticals Corporation, 180 Park Avenue, Building 105, Room
2W212, Florham Park, NJ 07936-
1080. DOI:
10.1177/0091270003262101
PHARMACOKINETICS AND PHARMACODYNAMICS
were 98.3% and 97.2%, respectively. Both the rate
andextent of imatinib absorption, as measured by Cmax,
partial AUC, and total AUC, were similar for the oral
solution and the imatinib capsule intended for the market.
The 400-mg oral dose of imatinib, as a capsule or a
solution, was completely absorbed and was almost
completely bioavailable (> 97%).
Keywords: Imatinib; STI571; bioavailability; oral solution;
capsule; pharmacokinetics
Journal of Clinical Pharmacology, 2004;44:158-162
©2004 the American College of Clinical Pharmacology
imatinib with the combination of IFN plus cytarabine
as initial therapy for newly diagnosed chronic-phase
CML. 12 This study demonstrated that imatinib
monotherapy is superior to the combination of IFN
and cytarabine, resulting in higher and more sustained
hematologic and cytogenetic response rates, longer
progression-free survival, and lower toxicity. Imatinib
is now approved for the first-line treatment of CML at
doses of 400 mg (for chronic-phase patients) and 600
mg (for patients in accelerated phase or blast crisis)
and is the preferred pharmacotherapeutic agent.13
Imatinib is also approved for use in patients with KIT
(CD117)– positive unresectable and/or metastatic
malignant gas- trointestinal tumor (GIST) at a dosage
of 400 or 600 mg daily.
The drug is orally administered as capsules con-
taining imatinib (STI571) equivalent to 100 mg of
imatinib-free base. Imatinib is a derivative of a 2-
phenylaminopyrimidine, a small-molecule antagonist
against protein-tyrosine kinases. It is highly soluble
in water and soluble in aqueous buffers at a pH of
5.5 or less. Pharmacokinetic (PK) results
demonstrate that imatinib is absorbed rapidly in
CML patients after oral
administration, with C reached at approximately 2
max
hours postdose,14 and the compound is detected in
plasma after 30 minutes. Following oral administration
of 14C-labeled imatinib, the radioactivity in plasma sug-
158  J Clin Pharmacol 2004;44:158-162
 IMATINIB ORALLY VERSUS INTRAVENOUS INFUSION
gests that more than 80% of the dose is absorbed.15
The absolute bioavailability of imatinib after oral
adminis- tration has not yet been reported. The aim of
the pres- ent study is to investigate the absolute
bioavailability and PK characteristics of a single oral
dose of 400 mg of imatinib, in the form of either four
100-mg capsules or an oral solution, compared with an
intravenous (i.v.) infusion of 100 mg of imatinib.
METHODS
Study Design
The study consisted of two parts, a pilot phase and the
main study. The i.v. dose for the main study was deter-
mined from the open-label pilot phase, in which 3
healthy volunteers received a single 60-minute i.v. in-
fusion of imatinib, 30 mg. The subjects in the pilot
phase did not participate in the main study.
The main study had a single-center, open-label,
three-period, three-treatment, randomized crossover
design. Twelve healthy male and female subjects were
to be enrolled. Each subject underwent a screening pe-
riod of maximum duration of 21 days followed by
three treatment periods. The subjects were randomly
as- signed to one of the six possible treatment arms
identi- fied as 400 mg of imatinib as a capsule, 400 mg
of imatinib as an oral solution, or 100 mg of imatinib
as a 60-minute i.v. infusion of Glivec® in different se-
quences. There was a minimum 7-day washout phase
between treatments. Each treatment period consisted
of a predose baseline evaluation, a drug treatment
phase, and a 96-hour postdose observation period.
Subjects who discontinued were to be replaced. All
subjects provided written informed consent.
Subjects were confined to the study center for at
least 12 to 14 hours before administration of study
drug and 24 hours after administration. In addition,
subjects were asked to adhere to the restrictions of no
strenuous physical exercise (e.g., weight training,
aerobics, foot- ball) for 7 days before dosing until after
study comple- tion and no alcohol consumption for 72
hours before dosing until after study completion.
Drug Administration
The study drug was prepared and packaged by
Novartis Pharma AG. It was supplied to the investiga-
tor as 100-mg hard-gelatin imatinib capsules and as
250-mg powder vials. For the imatinib solution, the
powder vials were reconstituted with 5 mL of water
for
PHARMACOKINETICS AND PHARMACODYNAMICS
injection, to yield a final concentration of 50 mg/mL.
To prepare the i.v. solution, 4 mL of this imatinib solu-
tion was made up to 40 mL with 5% glucose in a 50-
mL infusion pump syringe (Becton Dickinson, Franklin
Lakes, NJ); 6 mL of the solution was infused over 60
minutes during the pilot phase (30 mg/h) and 20 mL
during the main study (100 mg/h). To prepare the oral
solution, 8 mL of imatinib solution (50 mg/mL) was
added to tap water for a total of 125 mL.
Imatinib capsules or oral solution was administered
2 hours after breakfast. No fluid intake apart from the
fluid given at the time of drug intake was allowed from
2 hours before until 2 hours after dosing. Lunch and
dinner were served 4 and 12 hours after dosing,
respec- tively, and a large snack was served at 8 hours
after dosing.
Blood Sampling
Drug determination in plasma was analyzed from 5.5
mL of venous blood drawn from a forearm vein into
heparin-containing tubes at specific intervals. For the
i.v. administration, the time points were predose
and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 4, 6, 8, 12, 24,
36, 48, 72, and 96 hours from the start of infusion.
The 1-hour postinfusion sample was drawn
immediately before the end of the i.v. infusion. For
the two oral administra- tions, blood samples were
analyzed predose and at 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12,
24, 36, 48, 72, and 96 hours postdose. All samples
were centrifuged within 30 min- utes, and plasma
was kept frozen at –18°C or below, pending analysis.
Analytical Method
Plasma imatinib concentrations were determined us-
ing a high-performance liquid chromatography/tan-
dem mass spectrometry (HPLC/MS/MS) assay.16 This
method was validated for both monkey and human
plasma. Plasma samples were prepared using a C18
solid-phase extraction procedure (3M Empore C8 ex-
traction disk). Sample extracts were analyzed using
reversed-phase chromatography with a Waters Sym-
metry column (Waters Corp., Milford, MA) followed by
detection with a Sciex API 3000 mass spectrometer
(PE Biosystems, Foster City, CA). The lower limit of
quanti- fication was 4 ng/mL, and the assay was fully
vali- dated. The accuracy and precision from prestudy
vali- dation were 97.8%  6.4% at the lower limit of
quantification and 91.5%-102%  0.4%-8.2% over the
entire concentration range of 1 to 10,000 ng/mL.
159
 PENG ET AL

Table I Pharmacokinetic Measurements

AUClast Area under the curve from the time of dosing to the last measurable concentration
AUC0- Area under the plasma concentration-time curve from time zero to infinity
Cmax Maximum plasma concentration after single-dose administration
tmax Time to reach maximum concentration following drug administration
t1/2 Apparent terminal elimination half-life
CL Absolute clearance (total body clearance of drug from the plasma)
Vz Volume of distribution based on terminal phase

PK Analysis
The single-dose PK parameters were determined by a
noncompartmental method using WinNonlin® Pro
Version 3.0.17 The PK parameters measured are listed
in Table I.
The absolute bioavailability, as ratio F, was deter-
mined for the 400-mg capsule administration and for
the 400-mg oral solution:
F = AUC0- (Oral) • Di.v./(AUC0- (i.v.) • Dpo),
where Di.v. is the dose administered intravenously,
and Dpo is the dose taken orally.
Statistical Analysis
With the exception of t
max , which was analyzed
nonparametrically, differences between treatments
were evaluated by an analysis of variance (ANOVA).
For absolute bioavailability ratio F, antilogs of the
esti- mates of the differences for the capsule and
ampoule versus i.v. infusion, together with a 90%
confidence in- terval, were used to obtain a
confidence interval for the F value. The level of
significance was set to 0.05.
RESULTS
Subjects
A total of 17 subjects (14 men and 3 postmenopausal
or sterile women) were screened for the pilot phase
and main study. The subjects were ages 40 to 58 years,
had a mean body weight of 73.3  7 kg (range: 62-88
kg), and were in good health as determined by past
medical his- tory, physical examination, vital signs,
electrocardio- gram, and laboratory test results at
screening. Two sub- jects discontinued from the main
study: 1 because of a urinary tract infection not related
to the study drug and the other because of inability to
adhere to the treatment and evaluation schedule for
personal reasons. Their
data were not included in the final analysis. Three sub-
jects participated in the pilot phase, and 12 were
randomized in the main study.
Pilot Phase
Following the 1-hour infusion of imatinib 30 mg, mean
Cmax was 373 ng/mL. Predicted exposure after a 100-
mg infusion for 1 hour was estimated as 1243 ng/mL;
this is below the systemic exposure that is known to
be well tolerated in patients, and thus a dose of 100
mg was used for the main study.
Main Study
The absorption of imatinib after oral administration of
capsules or solution was rapid, with a median tmax of
2.5 and 2 hours, respectively. For each treatment, the
mean
plasma imatinib concentrations with time are shown
in Figures 1 and 2, and the PK results are summarized
in Table II. Systemic availability of imatinib after oral
administration either as capsules or solution was close
to 100%. Mean absolute bioavailability for the cap-
sules and the oral solution was 98.3% and 97.2%, re-
spectively (Table III). The rate and extent of absorption
of imatinib, as measured by Cmax, partial AUC, and total
AUC, were similar for the capsule and oral solution.
Disintegration of the capsule and dissolution of
imatinib in the gastrointestinal tract are therefore not
rate-limiting steps in the absorption process, and the
study results are consistent with the rapid in vitro dis-
solution shown for the capsule (data not shown). How-
ever, the coefficient of variation for Cmax (44% and 66%
for solution and capsule, respectively) and AUC (31%
and 51% for solution and capsule, respectively)
showed considerable intersubject variation.
Adverse Events
There were few adverse findings for safety and
tolerability, and no serious adverse events were re-
160  J Clin Pharmacol 2004;44:158-162
 IMATINIB ORALLY VERSUS INTRAVENOUS INFUSION

Table II Pharmacokinetic Parameters Following Administration

of Imatinib Orally as Capsule or Solution or by 60-Minute i.v. Infusion
Capsule (400 mg) Oral Solution (400 mg) i.v. Infusion (100 mg)

tmax (h)a 2.5 (1.0-6.0) 2.0 (1.5-4.0) 1.0 (0.5-1.0)

Cmax (ng/mL) 1822  1193 1848  805 1206  295
t1/2 17.9  3.1 18.3  2.7 21.9  4.3
AUC(0-2.5) (ng•h/mL) 2769  2362 3317  1466 1617  398
AUC(0-) (ng•h/mL) 32,640  16,501 30,729  9573 7836  2185
Vz/F (L) 382  194 385  167 —
Vz (L) — — 435  154
CL/F (L/h) 14.9  7.5 14.5  5.7 —
CL (L/h) — — 13.9  5.0
F, bioavailability.
a. Median (range); all other values are mean  standard deviation.

Table III Absolute and Relative Bioavailabilities of

Imatinib from Oral Capsule or Solution or from 60-Minute i.v. Infusion
Capsule (400 mg) Oral Solution (400 mg) i.v. Infusion (100 mg)

AUC(0-) (ng•h/mL) (arithmetic mean) 32,640 30,729 7836

AUC(0-) (ng•h/mL) (geometric mean) 29,607 29,261 7527
F (absolute bioavailability) (90% CI) 98.3% (87.3%-111%) 97.2% (86.3%-110%) Reference
F (relative bioavailability) (90% CI) Reference 98.8% (87.7%-111%) —
CI, confidence interval.

ported. One subject was withdrawn from the trial be-

cause of a urinary tract infection, as previously noted; 10000.0
Capsule Solution
i.v. infusion
this was not considered to be related to the study drug.
Data from this patient were not included in the final
analysis. The most frequently reported adverse events
were headache (experienced by subjects taking all 1000.0

dose forms) and mild pain or burning at the infusion

site. There were two cases of severe headache and one
in- stance of phlebitis following i.v. administration.
There were no clinically significant abnormalities in 100.0

0 10 20 30 405060 70 80 90 100
labora- tory values, vital signs, or Time (h)

electrocardiographic findings.
10.0
DISCUSSION

Imatinib capsules have been developed for the treat-

ment of CML and solid tumors. In Phase I/II clinical tri- 1.0
als, complete hematologic responses typically oc-
curred in CML patients treated with a dose of 350 mg
or more per day within 4 weeks after the initiation of
ther- apy.7,8 The approved dosage in CML and GIST is 0.1

400 or 600 mg daily. The present study was conducted Figure 1. Mean plasma concentration (log scale) with time after
to esti- mate the rate and extent of systemic ad- ministration of imatinib.
availability of the

parent compound. By comparing a solid-dosage form

(capsules) with an oral solution, we could also investi-
gate the influence of disintegration and dissolution profiles for imatinib capsules show rapid release of
on the absorption process. Owing to the high drug with almost com- plete dissolution within 10
solubility of imatinib, the in vitro dissolution minutes (data not shown).

PHARMACOKINETICS AND PHARMACODYNAMICS 161

 PENG ET AL
tor STI571 in a patient with a metastatic gastrointestinal stromal tu- mor.
N Engl J Med 2001;344:1052-1056.

1800
Capsule Solution
i.v. infusion
1600

1400

1200

1000

0
0 3 6 9 1215 18 21 24
800 Time (h)

600

400

200

Figure 2. Mean plasma concentration (linear scale) with time fol-

lowing imatinib administration.

The almost complete bioavailability of a 400-mg

oral dose of imatinib is indicative of high
permeability and a low hepatic extraction ratio.
Total plasma clearance of imatinib is about 14 L/h
(233 mL/min) and is only 18% of hepatic blood
flow (1.3 L/min)18 or 30% of hepatic plasma flow
(780 mL/min).
This study demonstrated considerable intersubject
variation in the pharmacokinetics of imatinib, with a
much lower intrasubject variability. The reasons for
this high variability are not yet fully understood and
may be attributed to intersubject variations in the
activ- ity of cytochrome P450 isoenzyme 3A4
(CYP3A4), a major enzyme in the biotransformation of
imatinib. Variability in CYP3A activity between
individuals is large19 and may in part contribute to
the large intersubject variability.

CONCLUSION

The study shows that in healthy volunteers ages 40

to approximately 60 years, the absolute
bioavailability of oral imatinib either as a solution
or in capsule form is higher than 97%. The oral
solution and the capsule dose form of imatinib are
bioequivalent with regard to AUC, Cmax, and tmax.

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