1. Pharmacokinetic interactions
among imatinib, bosentan
and sildenafil, and their
clinical implications in severe
pulmonary arterial
hypertension
Didier Renard,1
Thomas Bouillon,1
Ping Zhou,2
Gerard Flesch1
& Debbie Quinn3
1
Novartis Pharma AG, Basel, Switzerland 2
Novartis Horsham Research Centre, Horsham, West
Sussex, UK and 3
Novartis Pharmaceuticals, East Hanover, USA
Correspondence
Dr Didier Renard, Integrated Quantitative
Sciences - Pharmacometrics, Novartis
Pharma AG, Postfach, CH-4002 Basel,
Switzerland.
Tel: +416 1324 1863
Fax: +41 61 3241246
E-mail: didier.renard@novartis.com
----------------------------------------------------
Keywords
bosentan, drug–drug interactions,
imatinib, pharmacokinetics, pulmonary
arterial hypertension, sildenafil
----------------------------------------------------
Received
13 May 2014
Accepted
31 December 2014
Accepted Article
Published Online
7 January 2015
AIMS
This study characterized the population pharmacokinetics (PK) of
imatinib in patients with severe pulmonary arterial hypertension (PAH),
investigated drug–drug interactions (DDI) among imatinib, sildenafil
and bosentan, and evaluated their clinical implications.
METHODS
Plasma concentrations of imatinib, bosentan and sildenafil were collected
in a phase III study and were used to characterize the PK of imatinib in this
population. DDIs among the three drugs were quantified using a linear
mixed model and log-transformed drug concentrations.
RESULTS
The population mean estimates of apparent clearance (CL/F) and volume
(V/F) were 10.8l h–1
(95% CI9.2, 12.4l h–1
) and 267 l (95% CI 208, 326 l),
respectively. It was estimated that sildenafil concentrations increased, on
average, by 64% (95% CI32%, 103%) and bosentan concentrations by
51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased
concentrations of co-medications, treatment differences between
imatinib and placebo for change in 6 min walk distance and pulmonary
vascular resistance were relatively constant across the entire concentration
range for sildenafil and bosentan. Overall, higher concentrations of imatinib
and bosentan were not associated with increasing liver enzymes (serum
glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic
transaminase [SGPT]).
CONCLUSIONS
Population PKs of imatinib in patients with severe PAH were found
comparable with those of patients with chronic myeloid leukemia.
Imatinib was found effective regardless of the co-medications and
showed intrinsic efficacy beyond merely elevating the concentrations
of the co-medications due to DDIs. There was no evidence of increased
risk of liver toxicity upon co-administration with bosentan.
WHAT IS ALREADY KNOWN ABOUT
THIS SUBJECT
• Population PK of imatinib have been
characterized in patients with chronic
myeloid leukemia (CML) and
gastrointestinal stromal tumours (GIST).
• Imatinib improved exercise capacity and
haemodynamics in patients with advanced
PAH who remain symptomatic on at least
two drugs of the currently available drug
classes.
• PK interactions between bosentan and
sildenafil have been reported.
WHAT THIS STUDY ADDS
• Population PK of imatinib in severe PAH
were comparable with CML.
• Bosentan and sildenafil concentrations
were elevated on co-administration with
imatinib.
• Imatinib has intrinsic efficacy beyond
merely elevating plasma concentrations of
bosentan and sildenafil.
• There was no evidence of increased liver-
related toxicity with co-administration of
bosentan and imatinib.
British Journal of Clinical
Pharmacology
DOI:10.1111/bcp.12584
© 2015 The British Pharmacological Society Br J Clin Pharmacol / 80:1 / 75–85 / 75

2. Introduction
Pulmonary arterial hypertension (PAH) is a progressive
disease with poor prognosis, characterized by marked
and sustained elevation of pulmonary arterial pressure
(PAP), pulmonary vascular resistance (PVR) and incre-
mental pulmonary vasculopathy that ultimately leads to
premature death [1–4]. The endothelin, nitric oxide and
prostacyclin pathways are three physiological pathways
that play an important role in the pathophysiology of
PAH [5]. These pathways are primarily associated with
vasodilation and unregulated proliferation of pulmonary
artery vascular smooth muscle cells [2].
Currently three classes of drugs have been approved for
the treatment of PAH in Europe and the United States,
namely, prostacyclin analogues, endothelin receptor antag-
onists (ambrisentan, bosentan, tadalafil and epoprostenol)
and phosphodiesterase (PDE5) inhibitors (avanafil, sildena-
fil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil and
zaprinast). There is limited improvement in pulmonary
haemodynamics as the current therapeutic interventions
available, including bosentan and sildenafil, primarily tar-
get pulmonary vasodilatation, whereas PAH is a prolifera-
tive disease of small pulmonary resistance vessels. Thus,
mortality remains high among patients with PAH. The me-
dian survival of patients with idiopathic or heritable PAH is
<3years [6], despite current therapy, which highlights the
need for more treatment options [7–9].
Imatinib is a tyrosine kinase inhibitor (TKI) targeting
the Abelson tyrosine kinase (ABL1), together with
the Abelson-related kinase (ABL2) and the oncogenic
BCR-ABL fusion protein, platelet-derived growth factor
receptor (PDGFR)-α and β, discoidin domain receptor
(DDR) and the KIT receptor [4]. Imatinib is approved
for the treatment of various malignant disorders includ-
ing Philadelphia (Ph) chromosome-positive chronic my-
eloid leukemia (CML), acute lymphoblastic leukemia
and gastrointestinal stromal tumours (GIST).
Imatinib has been shown to inhibit certain cytochrome
P450 (CYP450)-metabolizing enzymes, and thus drug–drug
interactions (DDIs) may occur. Imatinib is a substrate for
CYP3A4/5 and has been shown, in vitro, to be a competitive
inhibitor of CYP3A4/5, CYP2C9 and CYP2D6 [4]. Drugs that
inhibit or induce the CYP3A4 isozyme have been shown to
alter imatinib pharmacokinetic (PK) exposure [10]. Sildenafil
is metabolized predominantly by CYP3A4 and to a minor
extent by CYP2C9 [11]. Bosentan is metabolized in the liver
by CYP3A4 and CYP2C9 [12, 13]. Mutual PK interactions
between bosentan and sildenafil have been reported in
healthy volunteers, and the dosage of each drug in a com-
bination treatment may have to be adjusted accordingly.
Thus, reciprocal PK interactions on co-administration of
these three drugs warranted investigation.
IMPRES [14], a multicentre, randomized, double-blind,
placebo-controlled, 24 week trial, evaluated imatinib in
patients with severe PAH. The primary objective of this
study included evaluation of safety and efficacy of
imatinib in patients with PAH. One of the secondary
objectives of this study was to assess the PK of imatinib
in this patient population and the potential for interac-
tion of imatinib on sildenafil and bosentan.
The present analysis was performed primarily to
characterize the population PK of imatinib in severe
PAH and to determine the PK interactions among
imatinib, bosentan and sildenafil. After this analysis con-
firmed the presence of significant interactions among
the three drugs, the effect of the intrinsic efficacy of ima-
tinib, as well as the potential for increased risk of hepa-
totoxicity when it is co-administered with bosentan,
was assessed.
Methods
Study participants
The study population consisted of 202 adult males and
females aged ≥18years, with a diagnosis of severe PAH, de-
fined as those who remained symptomatic, i.e. had WHO
functional class II-IV status, were on at least two PAH-specific
therapies and had a baseline PVR of ≥800dyn s cm-5
. PAH
could be either idiopathic or heritable (familial or sporadic).
It could be associated with (a) collagen vascular disease in-
cluding systemic sclerosis, rheumatoid arthritis, mixed con-
nective tissue diseases and overlap syndrome, (b) the use of
appetite suppressants or toxic compounds or (c) congenital
heart disease (≥1 year post-complete repair of atrial septal de-
fect, ventricular septal defect or posterior descending artery).
Study design and treatments
This was a multicentre, randomized, double-blind and
parallel group study in patients with PAH. After informed
consent was obtained, the patients were screened to
evaluate the pulmonary haemodynamics, and if found
suitable, were randomized in 1: 1 ratio to receive imatinib
(in 100 mg film-coated tablets) or placebo once daily. The
therapy was initiated with 200 mg imatinib for 2 weeks,
followed by 400 mg imatinib, if tolerated well, until
24 weeks. If 400 mg of imatinib was not tolerated, the
dose was down-titrated to 200 mg. Details of the study
design and main results are described elsewhere [14].
The study protocol was approved by ethics committees
and/or institutional review boards at each study centre
and each patient provided written, informed consent to
participate in the study.
PK assessments and monitoring
A sparse PK sampling approach was taken and plasma
samples were typically obtained at the following times
in the study: day 0 (first 200 mg once daily dose, at pre-
dose and between 0.5 and 3 h post-dose), day 14 (first
400 mg once daily dose, at pre-dose and between 0.5
and 3 h post-dose), day 28 (at pre-dose and between
D. Renard et al.
76 / 80:1 / Br J Clin Pharmacol

3. 0.5 and 3 h post-dose) and day 168 (at pre-dose, between
0.5 and 3 h post-dose, between 3 and 6 h post-dose and
between 6 and 8 h post-dose).
All samples were taken by either direct venipuncture
or via indwelling cannula inserted in a forearm vein. For
each plasma sample, 6 ml of blood were collected into a
tube containing heparin, inverted several times and cen-
trifuged at 1100 g for at least 10 min. Plasma samples
were separated into polypropylene screw-cap tubes
and frozen at –20 °C. All tubes were kept frozen until
shipment. All samples were carefully packed in suitable
packing material containing sufficient dry ice to keep
them frozen during shipment.
The parent compound imatinib and its metabolite,
CGP74588, were measured in plasma by validated liquid
chromatography-mass spectrometry (HPLC-MS/MS) assay
[15]. The limit of quantification for imatinib and its active
metabolite assays was 20ng ml–1
. The parent drug
bosentan and its major active metabolite, Ro 48-5033, were
determined by validated HPLC-MS/MS assays. The limit of
quantification for bosentan and its active metabolite was
1ng ml–1
. The parent drug sildenafil and its active N-
desmethyl metabolite were determined by validated
HPLC-MS/MS assays. The limit of quantification for sildenafil
and its active metabolite was 1ng ml–1
.
Statistical methods
Population PK analysis
The population PK of imatinib was described by a one
compartment disposition model with zero order input
and inter-individual variability (IIV) on CL/F and volume
of distribution (V/F). The covariate search included age,
gender, race, haemoglobin, white blood cell (WBC) count
and co-medications (CYP3A4 inhibitors such as sildenafil
and bosentan). Two covariates, presence/absence of
bosentan and haemoglobin concentrations, were
included in the final model. More details on methods
for covariate searching and validation of the population
PK model are separately provided as an online appendix.
Population PK analyses were performed with NONMEM
(version VI, Icon Development Solutions).
Drug–drug interaction assessment
Forgraphicalexploration, dose-normalized concentrations of
one drug were plotted vs. absolute concentrations of the
second drug in the presence or absence of the third drug.
Only concentrations at steady-state for all three drugs were
included, thus excluding day 0 (i.e. first dose of imatinib).
To quantify interaction effects more precisely, con-
centrations of sildenafil (respectively, bosentan) were
log transformed and analyzed using a linear mixed
model that included total daily dose and baseline
concentration of sildenafil (respectively, bosentan) as
continuous covariates, and indicator variables for the
presence/absence of bosentan (respectively, sildenafil)
and imatinib. Drug concentrations of sildenafil and
bosentan at baseline were calculated as the average of
the two concentrations obtained at day 0. The model
further included subject as a random effect. Geometric
mean ratios with 95% confidence intervals (CI) were de-
rived to quantify the mean fold difference in sildenafil
concentrations in the presence vs. absence of bosentan
or imatinib. A similar approach was used to investigate
the effects of bosentan and sildenafil on imatinib con-
centrations, with the analysis model including imatinib
dose (log transformed) as a covariate and indicator vari-
ables for the presence/absence of bosentan and sildena-
fil. Those analyses were performed in R version 2.10.1
using the LME function (NLME library).
The results were retrospectively contrasted with
those from a dedicated DDI study (unpublished data,
NCT01392469; http://clinicaltrials.gov/show/NCT01392469),
which was conducted at the request of health authori-
ties. This DDI study focused on characterizing the PK
effect of imatinib on the co-administered drugs bosentan
and sildenafil. Changes in exposure (AUC over dosing
interval) of sildenafil and bosentan, before and after
administration of imatinib (200 mg for 2 weeks followed
by 400 mg for 2 weeks), were used for this purpose.
Clinical implications of drug–drug interaction
findings
Graphical exploration to investigate relationships between
plasma concentrations of each drug to key efficacy and
safety variables was undertaken.
Results
Two hundred and two adult patients with severe PAH were
randomized to receive either imatinib (n=103) or placebo
(n=99). In total, 69 patients (67%) in the imatinib treatment
arm and 81 (81.8%) patients in the placebo treatment arm
completed the study. We refer to the original publication
[14] for additional details related to the study population.
The overall PK analysis dataset consisted of 751 measur-
able concentrations of bosentan, 1024 of sildenafil and 572
of imatinib collected from 191 PAH patients. Among these,
101 patients received at least one dose of imatinib, 165
received sildenafil and 114 received bosentan during the
study. Details of imatinib-treated patients who received
sildenafil and bosentan are presented in Table 1.
Population PKs of imatinib
The population PK dataset of imatinib is represented in
Figure 1, where dose-normalized concentrations at steady-
state are plotted vs. time after last dose administration.
Superimposed on this plot is a historical prediction from
the population PK model of imatinib in CML [16]. As it can
be seen, the curve and corresponding 90% prediction
PK analysis of imatinib, bosentan and sildenafil in patients with PAH
Br J Clin Pharmacol / 80:1 / 77

4. interval provide a reasonable description of the measured
concentrations of imatinib in PAH, suggesting that PKs in
these two different patient populations are quite similar.
This was further confirmed by fitting the same struc-
tural compartmental PK model (one compartment dis-
position model with zero order absorption) to the PAH
dataset. Parameter estimates of the final model for ima-
tinib are shown in Table 2. The apparent clearance
(10.8 l h–1
, 95% CI 9.2, 12.4 l h–1
) in the absence of
bosentan was similar to values previously reported in
CML (13.8 ± 0.5 l h–1
) and GIST (9.3 ± 1 l h–1
) patients
[16, 17]. The V/F (267 l, 95% CI 208, 326 l) was similar to
that in CML patients (252 ± 8 l) and approximately 45%
greater than in GIST patients (184 ± 14 l). Bosentan was
estimated to increase apparent imatinib clearance and
V/F by 46%, corresponding to a decreased exposure
(AUC) of approximately 30%.
Drug–drug interactions
Sildenafil concentrations tended to be reduced on
co-administration with bosentan and increased with
imatinib (Figure 2). The statistical analysis (Figure 3)
estimated that sildenafil concentrations, on average,
increased by 64% (95% CI 32%, 103%) in the presence
of imatinib and decreased by 44% (95% CI 30%, 56%) in
the presence of bosentan. The estimated combined
effect of bosentan and imatinib was null (ratio relative
to no drug co-administered = 0.92, 95% CI 0.68, 1.23).
Figure 3 also shows the estimated increase in sildenafil
exposure (AUC) after administration of imatinib (red
triangle), as determined in the dedicated DDI study. This
effect was consistent with the estimate from our own
analysis.
Increased bosentan concentrations were observed
on co-administration of bosentan with sildenafil or
imatinib (Figure 4). The statistical analysis (Figure 5)
estimated that bosentan concentrations, on average,
increased by 51% (95% CI 12%, 104%) in the
presence of imatinib and by 53% (95% CI 9%, 115%)
in the presence of sildenafil. The estimated combined
effect of sildenafil and imatinib was an increase in
bosentan concentrations of 132% (95% CI 46%, 269%).
Figure 5 also shows the estimated increase in
bosentan exposure (AUC) after administration of ima-
tinib (red triangle), as determined in the dedicated
DDI study. This effect was consistent with the estimate
from our own analysis.
On co-administration with bosentan, imatinib
concentrations tended to decrease (Figure 6). In addition,
there were no clear changes observed in imatinib
concentration on co-administration with sildenafil. The
statistical analysis (Figure 7) confirmed that imatinib con-
centrations, on average, decreased by 33% (95% CI 18%,
45%) in the presence of bosentan and did not change in
a statistically significant manner in the presence of sil-
denafil (ratio present : absent = 0.96, 95% CI 0.76, 1.22).
The estimated combined effect of sildenafil and
bosentan was a decrease in imatinib concentrations of
35% (95% CI 10%, 53%).
Clinical implications of DDI findings
The analysis data set consisted of 186 patients (imatinib
n = 94, placebo n = 92), which included measures of
efficacy (6 min walk distance (6MWD) and PVR) as well
Table 1
Number of patients per drug combination in population PK dataset.
Placebo (n = 90) Imatinib (n = 101)
Bosentan Bosentan
Sildenafil No Yes Sildenafil No Yes
No 0 10 No 5 11
Yes 36 44 Yes 36 49
Figure 1
Comparison of dose-normalized imatinib concentrations in PAH with
historical prediction in CML. Dose-normalized concentrations mea-
sured in the study (circles) were overlaid with a historical population
prediction (solid line, population median; coloured area, 90% predic-
tion interval) from the CML population model of imatinib.
Table 2
Parameter estimates of the final population pharmacokinetic model for
imatinib
Parameter Estimate (standard error)
CL/F (L/h) 10.8 (0.83) IIV: CV = 43%
V/F (L) 267 (30.0) IIV: CV = 64%
Fractional increase of CL/F and V/F due
to bosentan
0.46 (0.15)
Effect (power coefficient, b) of haemoglobin
on V/F and CL/F, i.e. (Hb/128)
b
with Hb in g/L
0.49 (0.25)
Duration of first order input (h) 1.52 (0.15)
CL/F, apparent clearance of drug from plasma; CV, coefficient of variation; Hb,
haemoglobin; IIV, inter-individual variability; V/F, apparent volume of distribu-
tion at steady-state
D. Renard et al.
78 / 80:1 / Br J Clin Pharmacol

5. as safety indicators (liver enzymes, serum glutamic
oxaloacetic transaminase [SGOT] and serum glutamic-
pyruvic transaminase [SGPT]).
To assess the potential impact of increased exposure
of co-medications on efficacy, 6MWD and PVR % changes
from baseline, evaluated after 24 weeks of treatment,
Figure 2
Effects of imatinib and bosentan on sildenafil concentrations. A, B: Log–log plot of dose-normalized sildenafil concentrations vs. (absolute) bosentan concen-
trations conditioned by absence (A)/presence (B) of imatinib. The median is indicated by a line summarizing dose-normalized concentrations of sildenafil in the
absence (left cluster) or over a range of concentrations (right cluster) of bosentan. Bos, bosentan. C, D: Log–log plot of dose-normalized sildenafil concentrations
vs. (absolute) imatinib concentrations conditioned by absence (C)/presence (D) of bosentan. The median is indicated by a line summarizing dose-normalized
concentrations of sildenafil in the absence (left cluster) or over a range of concentrations (right cluster) of imatinib. Ima, imatinib.
Figure 3
Estimated effects of imatinib and bosentan on sildenafil concentrations. Geometric mean of sildenafil concentrations with 95% confidence intervals in
the presence/absence of imatinib and/or bosentan (A) and mean relative effects on sildenafil concentrations for co-administration of imatinib and/or
bosentan vs. no co-administration (B). None, neither imatinib nor bosentan co-administered with sildenafil; Ima alone, imatinib co-administered; Bos
alone, bosentan co-administered; Ima + Bos, imatinib and bosentan co-administered.
◂, DDI study (geometric mean ratio for AUC over dosing interval)
PK analysis of imatinib, bosentan and sildenafil in patients with PAH
Br J Clin Pharmacol / 80:1 / 79

6. Figure 4
Effects of imatinib and sildenafil on bosentan concentrations. A, B: Log–log plot of dose-normalized bosentan concentrations vs. (absolute) sildenafil concen-
trations conditioned by absence (A)/presence (B) of imatinib. The median is indicated by a line summarizing dose-normalized concentrations of bosentan in the
absence (left cluster) or over a range of concentrations (right cluster) of sildenafil. Sil, sildenafil. C, D: Log–log plot of dose-normalized bosentan concentrations
vs. (absolute) imatinib concentrations conditioned by absence (C)/presence (D) of sildenafil. The median is indicated by a line summarizing dose-normalized
concentrations of bosentan in the absence (left cluster) or over a range of concentrations (right cluster) of imatinib. Ima, imatinib.
Figure 5
Estimated effects of imatinib and sildenafil on bosentan concentrations. Geometric mean of bosentan concentrations with 95% confidence
intervals in the presence/absence of imatinib and/or sildenafil (A) and mean relative effects on bosentan concentrations for co-administration
of imatinib and/or sildenafil vs. no co-administration (B). None, neither imatinib nor sildenafil co-administered with bosentan; Ima alone, imatinib
co-administered; Sil alone, sildenafil co-administered; Ima + Sil, imatinib and sildenafil co-administered.
◂, DDI study (geometric mean ratio for
AUC over dosing interval)
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80 / 80:1 / Br J Clin Pharmacol

7. were plotted against individually averaged concentra-
tions of sildenafil and bosentan (Figure 8).
Interpretation of those graphs requires caution as
they do not show typical concentration–response
relationships, as patients entered the study with some
co-medications already prescribed by their treating
physician. The interest of such displays primarily lies
in contrasting the placebo and imatinib responses over
Figure 6
Effects of bosentan and sildenafil on imatinib concentrations. A, B: Log–log plot of dose-normalized imatinib concentrations vs. (absolute) sildenafil concentra-
tions conditioned by absence (A)/presence (B) of bosentan. The median is indicated by a line summarizing dose-normalized concentrations of imatinib in the
absence (left cluster) or over a range of concentrations (right cluster) of sildenafil. Sil, sildenafil. C, D: Log–log plot of dose-normalized imatinib concentrations vs.
(absolute) bosentan concentrations conditioned by absence (C)/presence (D) of sildenafil. The median is indicated by a line summarizing dose-normalized
concentrations of imatinib in the absence (left cluster) or over a range of concentrations (right cluster) of bosentan. Bos, bosentan
Figure 7
Estimated effects of bosentan and sildenafil on imatinib concentrations. Geometric mean of imatinib concentrations with 95% confidence intervals in
the presence/absence of bosentan and/or sildenafil (A) and mean relative effects on imatinib concentrations for co-administration of bosentan and/or
sildenafil vs. no co-administration (B). None: neither bosentan nor sildenafil co-administered with imatinib; Bos alone, bosentan co-administered; Sil
alone, sildenafil co-administered; Bos + Sil, bosentan and sildenafil co-administered
PK analysis of imatinib, bosentan and sildenafil in patients with PAH
Br J Clin Pharmacol / 80:1 / 81

8. the range of co-medication concentrations. A key point
to emphasise is that the treatment difference varies
over the range of concentrations for sildenafil and
bosentan. If efficacy of imatinib was partly attributable
to increased exposure to sildenafil or bosentan, one
would expect to see increasing differences between
placebo and imatinib with higher concentrations of
the respective co-medications. However, as shown in
Figure 8, the treatment differences tended to remain rel-
atively constant over the range of co-medication concen-
trations, especially at the highest concentration range.
As hepatic AEs were to be expected based on the AE
profile of both bosentan and imatinib, and the combina-
tion of both drugs is a potential source for additive or
even synergistic interaction in this regard, we investi-
gated the potential impact of increased exposure of
Figure 8
Relationship of 6MWD and PVR per cent change from baseline, evaluated after 24 weeks of treatment, vs. averaged sildenafil (left) and bosentan (right)
concentrations. Percent changes from baseline in 6MWD (A) or PVR (B) after 24 weeks of treatment are plotted against the individually averaged silden-
afil (left) and bosentan (right) concentrations. Averaged concentrations were obtained as the geometric mean of all measurable plasma concentrations
of sildenafil or bosentan in each patient. Circles are for patients in the imatinib group and triangles for patients in the placebo group. Patients not re-
ceiving sildenafil (No Sil) or not receiving bosentan (No Bos) were assigned small random values for appearance on the logarithmic axes. In each plot, the
dashed line corresponds to a smooth (loess) fit to the placebo data and the solid blue line to the imatinib data. The horizontal boxplots (in the lower part
of each figure) refer to the distributions of the individually averaged sildenafil/bosentan concentrations in the placebo (Pbo) or imatinib (Ima) groups. In
each boxplot, the bold line is the median value, the edges of the box correspond to the 1st and 3rd quartiles (hence length of the box = inter-quartile
range), and the whiskers extend to the most extreme data point that is not more than 1.5 times the inter-quartile range from the box
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9. co-medications on the risk for hepatotoxicity. For this pur-
pose, SGOT and SGPT concentrations were plotted against
the corresponding trough concentrations of imatinib, both
in the presence or absence of bosentan (Figure 9). Overall,
there was no clear tendency of increasing liver enzymes
with higher concentrations of imatinib. Similar conclusions
hold when plotting liver enzymes vs. averaged bosentan
concentrations (results not shown).
Discussion
Population PK of imatinib in severe PAH were characterized
by similar CL/F and V/F compared with CML patients [16].
They were also comparable with those of patients with
GIST, although the estimated volume of distribution was
smaller in patients with GIST. Similar dosing regimens
appear to be effective in these different disease areas.
The major covariate relevant for imatinib in PAH was co-
administration of bosentan, which decreased the exposure
to imatinib and, therefore, does not pose an additional
safety risk. This leads to lower steady-state metrics in the
PAH population. Thus, typical trough values at steady-state
in the CML/GIST populations are approximately 1000ng
ml–1
. Our population model would predict a similar value
for a typical patient not receiving bosentan. However,
when taken across the study population, the averaged
value is approximately 700ng ml–1
, which reflects bosentan
usage in approximately 60% of the patients in our study.
In addition to co-administration with bosentan, a more
weakly significant relationship between haemoglobin and
apparent volume and clearance was identified. This is
consistent with findings in CML [16] and supported by
the known distribution of imatinib into erythrocytes
[18, 19]. Although other covariates were not identified as
statistically significant in the covariate search analysis, it
should be stressed that our dataset was considerably
smaller than that investigated by Schmidli et al. [16] and,
therefore, the results should not be misinterpreted as an
absence of effect (e.g. bodyweight on CL/F and V/F). An
effect of WBC count on PK parameters was most likely not
identified because of the different populations (PAH vs.
CML), their median WBC count (5.8 vs. 16.0 109
l–1
) and
vastly different distributions. We can further emphasize
that there was no evidence for a relevant PK difference be-
tween different races, including Japanese and other Asian
patients. Obviously, this involved small numbers of patients
and such conclusions cannot be considered definitive.
When focusing on potential DDIs among imatinib,
sildenafil and bosentan, we can first note that bosentan
was found to decrease sildenafil concentrations by ap-
proximately 50% and sildenafil to increase bosentan con-
centrations by approximately 50%, which is consistent
with previous reports [11, 20]. This is a first hint
supporting the validity of the sparse PK sampling ap-
proach within a phase III study to elucidate such a
complex question of PK interactions among the three
drugs. In this analysis, it was also found that, on average,
co-administration of imatinib resulted in increased con-
centrations of bosentan by 50% and sildenafil by 66%.
These results were confirmed by a retrospective compar-
ison with the results of a dedicated DDI study requested
Figure 9
SGOT/SGPT vs. steady-state trough concentrations of imatinib. Only SGOT (A)/SGPT (B) values coinciding with a trough measurement at a steady state
are plotted (the number of SGOT/SGPT measurements exceeded the number of steady-state trough concentrations). The presence/absence of bosentan
is indicated (shape and colour). The lines refer to loess smoothers through the respective groups. The shaded areas are 95% confidence intervals of the
smoothers. , bosentan; , no bosentan
PK analysis of imatinib, bosentan and sildenafil in patients with PAH
Br J Clin Pharmacol / 80:1 / 83

10. by health authorities to quantify the PK impact of ima-
tinib on co-administration of bosentan and sildenafil.
This unpublished study estimated the increase in silden-
afil exposure after administration of imatinib to be 70%
(90% CI 43%, 103%), and the corresponding increase in
bosentan exposure to be 40% (90% CI 23%, 59%). This
was again consistent with our own findings, which fur-
ther testifies to the validity of the conclusions based on
a sparse PK sampling approach to characterize PK inter-
actions among the three drugs.
Interestingly, the effects of bosentan and imatinib on
sildenafil cancelled out, bringing exposure close to that
observed in the absence of both the drugs. Sildenafil did
not have an apparent effect on imatinib concentrations.
However, bosentan, on average, decreased imatinib con-
centrations by approximately 30% regardless of the
presence of sildenafil. The estimated combined effect of
sildenafil and bosentan was a decrease in imatinib
concentrations by 35%, indicating that the effect of
bosentan on the PK of imatinib is independent of sildenafil
presence, and sildenafil does not impact on the PK of
imatinib.
Following characterization of the different PK interac-
tions among the three drugs, their clinical implications
were assessed. The key finding that imatinib increased co-
medication exposure immediately raises the question
whether the efficacy of imatinib is caused by enhancing
the effect of bosentan and sildenafil via increasing their ex-
posure. In this case, the effect of imatinib would be more
pronounced at high concentrations of the respective co-
medications. However, treatment differences between ima-
tinib and placebo for change of 6MWD and change of PVR
were relatively constant across the entire concentration
range for sildenafil and bosentan. Therefore, it is not
expected that an increase of either bosentan or sildenafil
exposure towards higher concentrations would lead to
improved efficacy. Even in the absence of either sildenafil
or bosentan, the effect of imatinib is as prominent as at
the highest concentrations of the respective drug, lending
strong support to its intrinsic efficacy beyond merely
elevating the concentration of the co-medications due to
DDIs. The ultimate proof would have been mono-
administration to patients with PAH, but this would have
required either withholding concomitant therapy from
patients already treated or substituting first line ther-
apy, which has been proven effective, with a study
drug of unknown therapeutic value.
As bosentan concentrations were, on average,
roughly doubled in the presence of sildenafil and ima-
tinib, the next question to be answered was the clinical
relevance of this increased exposure. With regard to po-
tential increased risk of hepatotoxicity, elevation of trans-
aminase levels has been reported, which occurred in 14%
of patients receiving 250 mg twice daily of bosentan, 4%
of those receiving 125 mg twice daily of bosentan and
3% of those receiving placebo [13]. Overall, in our study,
the occurrence of newly occurring or worsening liver
function tests (defined as >3 × ULN in SGOT, or >3
× ULN in SGPT or >1.5 × ULN in alkaline phosphatase or
>1.5 × ULN in total bilirubin) was 8% (eight of 102
patients) in the imatinib group vs. 10% (10 of 98 patients)
in the placebo group. When restricting to patients who
were taking bosentan, corresponding numbers were
12% (seven of 59 patients) in the imatinib group and
10% (five of 49 patients) in the placebo group. A trend
of increased frequency of liver test abnormalities was
therefore seen in this subgroup, but such a difference is
hardly conclusive based on the small patient numbers.
In addition, an exposure-dependent increase to bosen-
tan or imatinib was not evident for any of the liver trans-
aminases in our study. In conclusion, there is no clear
evidence of increased risk of elevated enzymes when
co-administering bosentan and imatinib. However, the
lack of significant elevated enzymes in our relatively
small study should not be taken as evidence for the
overall absence of this effect.
In conclusion, parameters of the population PK
analysis of imatinib in patients with severe PAH were
found comparable with those in patients with CML. Con-
centrations of bosentan and sildenafil were elevated on
co-administration with imatinib. Bosentan, on average,
decreased imatinib concentrations, whereas sildenafil
had no effect on imatinib concentrations. Beyond merely
elevating the concentrations of the co-medications,
further exploration of the data supports intrinsic efficacy
of imatinib in this patient population. While our DDI
assessment based on sparse PK data was quite robust
and corroborated by a separate DDI study, further
studies would be needed to confirm the lack of clinical
relevance of those PK interactions.
Competing Interests
This work was funded by Novartis Pharmaceuticals AG,
Basel, Switzerland. All authors have completed the
Unified Competing Interest form at http://www.icmje.
org/coi_disclosure.pdf (available on request from the
corresponding author) and declare no support from any
other organization for the submitted work, no financial
relationships with any organizations that might have an
interest in the submitted work in the previous 3 years
and no other relationships or activities that could appear
to have influenced the submitted work. All the authors
are employees of Novartis and declare no conflict of
interest. All the authors participated in the analysis and
interpretation of data and critical revision of the
manuscript. The authors were assisted in the preparation
of the manuscript by Snigdha Santra, Siddharth
Vishwakarma, Amit Bhat and Kevin Roche who provided
medical writing assistance and subsequent revisions
based on authors’ feedback.
D. Renard et al.
84 / 80:1 / Br J Clin Pharmacol

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Supporting Information
Additional Supporting Information may be found in the
online version of this article at the publisher’s web-site:
Appendix S1
Population PK modeling
PK analysis of imatinib, bosentan and sildenafil in patients with PAH
Br J Clin Pharmacol / 80:1 / 85