PK

No
.

Autho
r

2.

Year

Study design and

procedure

Sample
collection

Jounal

Issue

Objective

Subject

Sample analysis

Abbas, 201
R., et
1
al.

Journal of
clinical
pharmacolog
y

Effect of
ketoconazole on
the
pharmacokinetic
of oral bosutinib
in healthy subject

-To evaluate the effects

of concomitant
administration of
ketoconazole on the
pharmacokinetic profile
of a single dose of
bosutinib in healthy
subjects
- To assess the safety
and tolerability of single
doses

Healthy men and

woman of nonchildbearing
potential aged 18 to
50 years: BMI 18-30
kg/m2, BW >/=50 kg

- Open label, randomized,

2-period crossover study
- Subjects received a
single oral dose of
bosutinib 100 mg alone
(Treatment A) and in
combibation with
multiple oral dose ok
ketoconazole 400 mg
(Treatment B)
- Subjects were
ranmdomlr assigned to 1
of 2 treatment sequences
for study periods 1 and 2
(Treatment A followed by
treatment B or treatment
B followed by treatment
A)

4 ml venous
blood
samples
were
collected
into
potassium
EDTAtreated
tubes at
predose (0
hr), 0.5, 1, 2,
3, 4,6, 8, 12,
18, 24, 36,
48, 60, 72
and 96 hr
after
bosutinib
administrati
on

- Sample were
analyzed for
bosutinib by a
validated
LClMS/MS
- LOQ 1 ng/ml

Abbas, 201
R., et
2
al.

Cancer
Chemother
Pharmacol

A phase I
ascending singledose study of the
safety,
tolerability, and
pharmacokinetics
of bosutinib in
healthy adult

- To support clinical
development, a doseescalation and foodeffect evaluation of
safety, tolerability, and
pharmacokinetics of
bosutinib in healthy
adults

-Healthy men and

woman aged 18-50
years
-Inclusion criteria:
non-childbearing
potential, body mass
index in the range of
18.0-30.0 kg/m2,

- A randomized, doubleblind, inpatient, placebocontrolled, ascending

single dose, parallel group
study of oral bosutinib
composed of two study
groups
1) a fasted group with 3

- Venous
blood
samples (5
mL each) for
quantitation
of bosutinib
concentrati
ons were

- Sample were
analyzed by
using LC/MS/MS
assay to
measure the
bosutinib
conentrations in
the plasma

No
.

Autho
r

Year

Jounal

Issue

Objective

subjects

3.

Abbas, 201
R., et
2
al.

Clinical
therapeutics

Ascending SingleDose Study of the

Safety Prole,
Tolerability, and
Pharmacokinetics
of Bosutinib
Coadministered
With
Ketoconazole to
Healthy Adult
Subjects

To assessed the safety

prole, tolerability, and
pharmacokinetics of
different dose
combinations of
bosutinib
coadministered with
ketoconazole in healthy
adults, and determined
whether
supratherapeutic
concentrations of
bosutinib can be
achieved with

Subject

Study design and

procedure

Sample
collection

Sample analysis

body weight >/= 50

kg, non-smokers or
smokers <10
cigarettes/day who
abstained from
smoking during the
inpatient stay
exclusion criteria:
significant
cardiovascular,
hepatic, renal, or
hematologic
diseases

doses cohorts (bosutinib

200, 400, and 400 mg
expanded dose)
2) a fed group with 4
doses cohorts (bosutinib
200, 400, 600, 800, 1000
and 1200 mg)
The fasted subjects fasted
overnight for >/= 10 h
before administration of
bosutinib or placebo.
The fed subjects were
given were given a highfat breakfast followed by
administration of
bosutinib or placebo

collected on - LLQ 1 ng/mL

study day 1
within 2 h of
dose
administrati
on (0 h) and
at 0.5, 1, 2,
3, 4, 6, 8,
12, 18, 24,
36, 48, 60,
72, and 96 h
after dose
administrati
on

Healthy men and

women aged 18 to
50 years of nonchildbearing
potential; BMI 18.0
to 30.0 kg/m2 BW
>/=50 kg and
nonsmokers or
smokers of 10
cigarettes per day
who abstained from
smoking during the
inpatient stay.

- Randomized, Phase I,
double-blind, sponsorunblinded, placebocontrolled, inpatient,
sequential-group study Single oral doses of
bosutinib 100, 200, 300,
400, 500, and 600 mg or
placebo were
administered with
ketoconazole and food on
day 1; daily single oral
doses of ketoconazole
400 mg were

3 ml venous
blood were
collected
into
potassium
EDTAtreated
tubes on
study day 1
within 1
hour before
dose
administrati
on (0 hour)

The bosutinib
concentrations
were measured
in the plasma
samples by using
a validated LCMS/MS assay.

No
.

Autho
r

Year

Jounal

Issue

Objective

Subject

ketoconazole.

4.

Hsyu,
P. H.,
et al.

201
3

Cancer
Chemother
Pharmacol

Pharmacokineticpharmacodynami
c relationship of
bosutinib in
patients with
chronic phase
chronic myeloid
leukemia

- To evaluate potential
bosutinib
pharmacokineticpharmacodynamic
relationships

- Patients with
newly diagnosed
</=6 months Ph+ CP
CML and no prior
antileukemia
treatment (except
anagrelide or
hydroxyurea)
- patients with
confirmed Ph+
leukemia and
resistance or
intolerance to prior
imatinib therapy

Study design and

procedure

Sample
collection

administered on days 1
and 1 through 4.

and at 0.5,
1, 2, 3, 4, 6,
8, 12, 24,
36, 48, 72,
and 96
hours after
dose
administrati
on.

- The first study was a

randomized, open-label,
active-controlled (versus
imatinib) phase 3 trial,
Bosutinib 500 mg was
administered once daily
with food.
- The second study was an
open-label, two-part,
phase trial of bosutinib
in patients with
confirmed Ph+ leukemia
and resistance or
intolerance to prior
imatinib therapy; only
patients with CP CML
were included in the
current analysis.
- Part 1 was a doseescalation study of
bosutinib 400-600 mg

- The final
pharmacoki
netic model
was a twocompartme
nt model
with firstorder
elimination,
and an
absorption
lag
- AUC,
Cmax, Cmin
used in the
current
analysis
were
derived
from a
population

Sample analysis

Measure
absortion but
not indicated on
which
instrument used

No
.

Autho
r

Chiaki
Nakas
eko.,
et al.

Year

201
5

Jounal

International
Journal of
Hematology

Issue

A phase 1/2 study

of bosutinib in
Japanese adults
with Philadelphia
chromosomeposi
tive chronic
myeloid leukemia

Objective

To presents
the results of an ongoing
phase 1/2 study
evaluating the
safety, pharmacokinetics
(PK), and efficacy of
bosutinib in
Japanese patients with
Ph+ CP CML
resistant/refractory or
intolerant to imatinib.

Subject

63 Japanese
patients with
Philadelphia
chromosomepositiv
e
(Ph+) chronic-phase
(CP) or advancedphase
chronic myeloid
leukemia (CML)
patients
resistant/intolerant
to previous imatinib
(2L) or
imatinib+dasatinib/
nilotinib (3L)

Study design and

procedure

Sample
collection

administered OD with
food to determine the
recommended starting
dose for Part 2
- Part 2 evaluated the
safety and efficacy of
bosutinib 500 mg OD with
food

PK model.

Screened for
enrollment(Non-RCT),
open-label, 2-part, phase
1/2 study
in Japanese patients with
Ph+ CP CML that is
resistant/
refractory or intolerant to
imatinib

Blood
samples for
PK analysis
were
collected
before and
1,
2, 3, 4, 6, 8,
24 and 48 h
after
bosutinib
administrati
on on
day 1, and
before and
1, 2, 3, 4, 6,
8, and 24 h
after
administrati
on
on day 15.

Part 1 was a doseescalation

study of bosutinib to
evaluate safety,
maximum tolerated
dose (MTD), and PK
parameters.
Patients were enrolled
following a 3+3 doseescalation
design through 3 dose
levels of bosutinib: 400,

Sample analysis

measure

No
.

Autho
r

Year

Jounal

Issue

Objective

Subject

Study design and

procedure

Sample
collection

Sample analysis

500, and
600 mg.

Part 2 evaluated clinical

efficacy through the rate
of major cytogenetic
response
(MCyR).

Abbas, 201
R., et
3
al.

Cancer
Chemother
Pharmacol

Evaluation of the
pharmacokinetics
and safety of
bosutinib
in patients with
chronic hepatic
impairment and
matched
healthy subjects

To evaluated the
pharmacokinetics and
safety of
bosutinib in patients
with chronic hepatic
impairment and
matched healthy
subjects.

-Healthy and
hepatically impaired
men and
nonpregnant
women aged 1865
years
- nonchildbearing
potential (surgically
sterile or
postmenopausal for
C1 year);
-sexually active men
had to agree to use
contraception
during the study and
for
12 weeks after
administration. Hepatically impaired

-open-label, single-dose,
parallel-group,inpatient,
nonrandomized study
-Patients with hepatic
impairment were
matched with healthy
subjects by age (within 5
years), sex, body mass
index (BMI; within 10 % at
screening), and, if
possible,smoking habits.
-Each participant received
a single 200-mg (2 9 100mg tablets) oral dose of
bosutinib in the morning
of study day 1 no later
than 5 min after the
completion of breakfast.
- follow-up visit within 4-7

Blood
samples (3
mL) were
obtained
within 1 h
before
bosutinib
administrati
on, at 0.5, 1,
2, 3, 4, 6, 8,
12, 24, 36,
48, 72, and
96 h after
administrati
on and at
the follow
up
visit

-Plasma
samples were
analyzed for
concentrations
of bosutinib and
its metabolites
[M2
(oxydechlorinate
d bosutinib) and
M5
(N-desmethyl
bosutinib)] by
liquid
chromatography
/tandem
mass
spectrometry
-The plasma
concentration

No
.

Autho
r

Year

Jounal

Issue

Objective

Subject

Study design and

procedure

Sample
collection

patients had to be of days

Child-Pugh classes A, B, or C, and the
etiology had to be
chronic alcoholism,
chronic viral
hepatitis (B,
C),nonalcoholic
steatohepatitis,
autoimmune
hepatitis, Wilson
disease, alpha-1
antitrypsin
deficiency, glycogen
storage diseases, or
galactosemia.
7

Abbas, 201
R., et
3
al.

Clin Drug
Investig

A Clinical Study to
Examine the
Potential Effect of
Lansoprazole
on the
Pharmacokinetics
of Bosutinib when
Administered
Concomitantly to
Healthy Subjects

To evaluate
the effect of
lansoprazole, a gastric
proton pump inhibitor,
on the pharmacokinetics
and safety of bosutinib.

-men or women of
non-childbearing
potential aged 18
50 years inclusive at
screening.
-Women must have
been either
surgically sterile
(hysterectomy
and/or
oophorectomy) or
postmenopausal for
C1 year (with

-a phase I, open-label,
non-randomized, single
site (in Miami, FL, USA),
inpatient/outpatient
study of 24 healthy
subjects.
-6 week treatment
iincluded a screening
evaluation within
3 weeks before
administration of the first
bosutinib dose, a 5-day
(4-night) inpatient period,

Sample analysis
data for
bosutinib,M5,
andM2
were analyzed
for each
participant using
noncompartmen
tal
methods with
WinNonlin.

Blood
samples (3
mL) were
collected on
Days 1 and
15
within 2 h
predose and
at 1, 2, 3, 4,
5, 6, 8, 10,
12, 18, 24,
36, 48, and
72 h

Bosutinib
plasma
concentrations
were analyzed
by a validated
highperformance
liquid
chromatography
(HPLC)/
tandem mass
spectrometry
assay

No
.

Autho
r

Year

Jounal

Issue

Objective

Subject
follicle-stimulating
hormone C38
mIU/mL)
-Sexually active men
must have
agreed to use a
medically
acceptable form of
contraception
during the study and
continued its use for
12 weeks after
last dose
administration.
- All subjects must
have weighed
C50 kg, with a body
mass index (BMI) of
18.032.0
kg/m2, and been
determined to be
healthy on the basis
of
screening
evaluations
-non-smokers or
smokers of \10
cigarettes per day,
and
must have been able
to abstain from

Study design and

procedure

Sample
collection

an 8-day outpatient
postdose
washout, and a 6-day (5night) inpatient period
- Each study participant
received a single oral
dose of bosutinib 400 mg
alone on Day 1 and then a
single oral dose of
lansoprazole 60 mg
on Day 14 and a
combination of bosutinib
400 mg plus
lansoprazole 60 mg
administered
concomitantly on Day 15
.

Sample analysis

No
.

Autho
r

Year

Jounal

Issue

Objective

Subject
smoking during the
inpatient stay.

Members
1. Tamakorn

Tiacharoen

ID: 533150092-1

2. Piyamaporn Uttaranakorn

ID: 533150096-3

3. Pornprapa

Panida Direkpok

ID: 533150100-8

4. Sarat

Kaewmulniem

ID: 533150134-1

5. Nudee

Chaleechiangpin

ID: 533150170-7

6. Kantisa

Boonserm

ID: 533150257-5

7. Sunisa

Klaichanthong

ID: 533150260-6

8. Hongkamon Sawangsiriwan

ID: 533150261-4

Study design and

procedure

Sample
collection

Sample analysis