Lung Deposition and Pharmacokinetics of Nebulized
Cyclosporine in Lung Transplant Patients
T.E. Corcoran, PhD,1,* R. Niven, PhD,2,* W. Verret, PhD,2S. Dilly, MBBS, PhD,2and B.A. Johnson, MD1
Background: Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection.
Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of
the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST).
Methods: Ten patients received 300mg of CIS (62.5mg/mL CsA in propylene glycol) admixed with 148MBq of
Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream?
disposable jet nebulizer. Deposition was assessed using a dual-headed gamma camera. Blood samples were
collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis
of the resulting blood concentration versus time profiles was performed.
Results: The average total deposited dose was 53.7–12.7mg. Average pulmonary dose was 31.8–16.3mg, and
stomach dose averaged 15.5–11.1mg. Device performance was consistent, with breathing maneuvers influ-
encing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6–11.2 vs.
8.3–5.2mg; p¼0.03). Blood concentrations declined quickly from a maximum of 372–140ng/mL to
15.3–9.7ng/mL at 24hr post dose. Levels of AUC(0–24) [area under the concentration vs. time curve from 0 to
24hr] averaged 1,493–746ng hr/mL. On a three times per week dose regimen, this represents <5% of the
weekly systemic exposure of twice per day oral administration.
Conclusions: Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled
aerosol. Systemic levels are small relative to typical oral CsA administration.
Key words: lung transplant, inhaled cyclosporine, aerosol deposition
ients.(1–6)Early studies postulated that direct immunosup-
pressive treatment of the lungs would decrease the incidence
of acute rejection events, which are a known risk factor for
chronic rejection (bronchiolitis obliterans), the most signifi-
cant cause of mortality after the first post–lung transplant
year.(7,8)However, the results of a single-center, placebo-
controlled study with inhaled CsA published in 2006 showed
distinct improvement in chronic rejection-free survival that
was not associated with any change in acute rejection rate.(9)
The same formulation, cyclosporine inhalation solution (CIS),
which contains 62.5mg/mL CsA in propylene glycol, was
number of studies have clinically evaluated the effects
of inhaled cyclosporine (CsA) in lung transplant recip-
recently evaluated in a multicenter, randomized, controlled
study (CYCLIST) to evaluate efficacy and safety in improving
bronchiolitis obliterans syndrome (BOS)–free survival fol-
aerosol treatments per week on alternate days with one rest
day. The aerosol delivery system and conditions of delivery
were modestly different from those previously used.
The unique anatomy of lung transplant recipients and the
potential for compromised respiratory function and lung
disease necessitate a careful evaluation of pulmonary dosing.
To evaluate delivery performance and systemic exposure
after aerosol administration, 10 subjects in CYCLIST were
asked to participate in a pharmacoscintigraphy substudy.
In this study, pulmonary dosing and 24-hr pharmacoki-
netics were evaluated after a single 300-mg (nominal dose)
1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
2APT Pharmaceuticals, Burlingame, CA 94010.
*T.E.C. and R.N. contributed equally to this work.
JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY
Volume 27, Number 3, 2014
ª Mary Ann Liebert, Inc.
treatment with CIS. Here we detail the techniques used and
report on the results of the study.
Materials and Methods
Preclinical studies of Tc-DTPA with CsA
Deposition scintigraphy techniques rely on a relationship
between active drug dose and radioactive counts from an
externally detectable radiopharmaceutical. Here we have
used technetium-99m bound to diethylenetriaminepen-
taacetic acid (Tc-DTPA) as a radiopharmaceutical deposition
analogue. To demonstrate a robust relationship between CsA
dose and radioactive counts across a range of aerosol sizes,
we nebulized CIS with a small added volume of Tc-DTPA
(148MBq in <0.3mL) and collected the aerosol using a Next
Generation Impactor (NGI; MSP Corporation, Shoreview,
MN). After 3min of collection time, radioactivity was mea-
sured in each collection cup. The cups were then washed out
using 50mL of methanol, and the concentration of CsA was
measured in each sample by high-performance liquid chro-
matography (HPLC). The percentage of collected CsA dose
was then compared with the radioactivity in each aerosol
size range. Five studies were performed and averaged. Cal-
culations of mass median aerodynamic diameter (MMAD)
and geometric standard deviation (GSD) were performed
based on NGI data. Laser diffraction measurements of
aerosol size were also performed using a Malvern Mas-
tersizer S (Malvern Instruments, Worcestershire, UK). Mea-
surements were made at 30-sec intervals over the first 3min
of operation and averaged. Two different nebulizers (same
model) were used. Volume median diameters (VMD) are
reported. GSD was calculated as VMD/84.1% volume di-
ameter. Measurements were made in open-air conditions
using a vacuum source to draw the aerosol through the
CIS was supplied in sterile glass vials at a concentration of
62.5mg/mL in propylene glycol (DSM Pharmaceuticals,
Parsippany, NJ). The minimum vial fill is 5.2mL (325mg of
CsA) of which approximately 4.8mL (300mg of CsA) is
dispensed into the nebulizer reservoir prior to dosing.
Aerosol was generated using a Sidestream?disposable jet
nebulizer (Philips-Respironics, Parsippany, NJ). The nebu-
lizer ‘‘T’’ outlets were connected to a high-efficiency partic-
ulate air (HEPA) exhalation filter and a mouthpiece without
an exhalation vent. A Mobilaire?compressor (Invacare,
Elyria, OH) was used. This compressor provides adjustable
air pressure and was set to 30 psig. Tc-DTPA was supplied in
sterile saline volumes of <0.3mL. This low volume of
aqueous solution is below the threshold of precipitation of
CsA in the final mixture.
The study protocol was approved by the Institutional
Review Boards of the University of Pittsburgh and of the
Cleveland Clinic. Subjects in this substudy were already
enrolled in the CYCLIST study—a Phase 3, multicenter,
randomized, controlled study designed to evaluate the effi-
cacy and safety of CIS in improving survival and preventing
BOS when given prophylactically to lung transplant recipi-
ents in addition to their standard immunosuppressive regi-
men (NCT00755781). A total of 10 male subjects were
consented and enrolled in the study (Table 1). By protocol,
the immunosuppressive regimen of the patients did not in-
clude oral CsA, and all patients were required to be on a
stable regimen of at least 250mg of CIS for ‡3 months prior
to the deposition study date. All subjects exhibited stable
lung function at the time of investigation (Table 2).
Substudy design and procedures
All study procedures were carried out at the University of
Pittsburgh Medical Center. The primary goal of the study
was to define the pharmacokinetics of CIS. The secondary
goal was to measure the total and regional deposition of CIS
using scintigraphic procedures. Subjects were admitted to
the Clinical Translational Research Center for a period of
36hr during which all procedures were performed.
Prior to dosing, a physical exam was completed, the chest
thickness was measured, a venous catheter was placed in a
peripheral vein, and a 2-mL predose blood sample was
collected. Subjects who used Chloraseptic?spray and/or
albuterol (by metered dose inhaler) as part of their normal
pre-CIS dosing routine also used this medication for the
substudy. A full vial of CIS was dispensed into the nebulizer
and admixed with 148MBq (4mCi) of Tc-DTPA (*0.3mL).
A HEPA exhalation filter collected excess aerosol generated
by the nebulizer and any dose exhaled by the subject. This
filter was replaced during dosing every 10min or upon re-
quest by the patient. Stoppage for coughing or rest periods
was allowed, and the additional dosing time was recorded.
Patients inhaled the aerosol in a seated position, and poste-
rior images were acquired throughout the dosing period.
Immediately after dosing, patients were asked to lie down
and both anterior and posterior gamma camera images were
simultaneously collected. This was followed by a Tc-DTPA
clearance measurement that included the sequential collec-
tion of posterior images over a 25-min period. Finally, a
xenon-133 ventilation scan was completed. After the com-
pletion of aerosol administration, blood samples of 2mL
Table 1. Patient Characteristics
Subject #123456789 10
Time from transplant (days)
DLT, double-lung transplant; SLT, single-lung transplant.
NEBULIZED CYCLOSPORINE IN LUNG TRANSPLANT PATIENTS179
were collected at 15, 30, 45, and 60min and at 2, 4, 8, 12, and
24hr, mixed in EDTA-coated tubes, transferred to cryovials,
and stored at -20?C prior to shipping to a central laboratory
(Covance Central Lab Services, Indianapolis, IN) for analysis
of CsA concentrations. Subjects were domiciled in the re-
search center overnight and were then discharged after the
last sample was collected.
The first five subjects evaluated were not given any spe-
cific instructions on how to breathe during aerosol delivery
at the time of scintigraphy testing. However, these subjects
did receive general instructions on nebulizer use at the time
of randomization in the CYCLIST study, including one-on-
one training by study staff, as well as a complementary in-
struction booklet and video. The last five subjects were given
verbal reinforced instruction on breathing maneuvers im-
mediately prior to scintigraphy dosing. The instructions in-
cluded the use of slow inhalations with a brief pause ahead
of exhalation. Subjects were also shown example images
from other deposition studies to demonstrate the importance
of proper breathing technique.
The total drug dose delivered to the subject was deter-
mined using a scintigraphy mass balance technique. The
radioactivity added to the nebulizer was measured prior to
aerosol delivery using a nuclear medicine dose calibrator.
After the dose was delivered, radioactivity was again as-
sessed in the nebulizer, filters, and other delivery system
components. Care was taken to ensure that the breathing
circuit was ‘‘closed’’ during aerosol delivery. The total
amount of radioactivity not recovered from the delivery
system was assumed to be deposited in the subject. The total
deposited CsA dose was then determined based on the
percentage of radioactivity delivered to the subject and the
starting CsA dose in the nebulizer. Emitted dose was cal-
culated based on the percentage of radioactivity that re-
mained in the nebulizer after delivery. Regional doses were
then determined from anterior and posterior gamma camera
images (256·256 pixels) collected after delivery. Images
were exported as DICOM files and analyzed using ImageJ
(NIH, Bethesda, MD). Lung perimeters were defined using
equilibrium xenon gas images applied to Tc-DTPA deposi-
tion images. Deposited activity was divided into zones in-
cluding mouth, trachea–esophagus, stomach, and right and
left lung. Lung images were further divided into central and
peripheral zones. The central zone was rectangular with one-
half the height and width of a rectangle outlining the whole
lung image. It was positioned on the medial edge of the
whole lung image at approximately mid-height. Counts from
anterior and posterior images were background corrected
and then combined in each zone using the geometric mean to
account for differences in distance between the individual
camera heads and the organs being measured. (A single
camera head would underestimate dose in organs located
further from its surface.) Central-to-peripheral dose ratio
(C/P) is the ratio of technetium-99m counts in the central
and peripheral zones without normalization by lung volume.
The average of the left and right lungs is reported.
DTPA is an absorbable molecule, and different absorption
rates may exist in different analysis zones.(10)Correction for
this effect was performed by measuring the clearance rate of
DTPA from the individual analysis zones for 25min after
delivery. The relative clearance rates for each zone were
determined and fit to exponential curves. The relative effect
of absorption at the midpoint of the treatment time was then
determined, and counts by zone were adjusted proportion-
ally. A final adjustment was performed to correct for dif-
ferences in attenuation based on measurements of chest
thickness, as previously described.(11)The percentage of
corrected counts by zone was applied to the total deposited
dose, as previously determined through mass balance tech-
niques, and CsA doses by zone were calculated.
Blood samples were processed for and analyzed by vali-
dated HPLC methodology using tandem mass spectrometry
detection. Blood concentration versus time profiles for CsA
were generated, and pharmacokinetic parameters including
Tmax, Cmax, t1/2, AUC(0–24), and MRTniwere calculated for
each subject together with summary statistics. [Tmax=time to
maximum concentration, Cmax=maximum blood concentra-
tion, t½=half-life, AUC(0–24)=area under the concentration
vs. time curve from 0 to 24hr, MRTni=mean residence time
(noninstantaneous).] These noncompartmental model esti-
mates were generated using WinNonlin (Pharsight, Sunny-
Preclinical studies of Tc-DTPA with CsA
Figure 1 shows percentage comparisons of CsA drug mass
(as assessed by HPLC) and radioactivity associated with Tc-
DTPA, by NGI stage. Figure 2 compares percentages of drug
captured with percentages of radioactivity captured across
all the stages. A strong linear relationship is demonstrated
between radioactivity and CsA drug mass. The MMAD of
the aerosol when calculated based on measurements of drug
Table 2. Lung Function Values
Subject #123456789 10
% of predicted
FEV1 max (L) during CYCLIST
FEV1/FVC ratio (%)
CYCLIST is a randomized, controlled trial to evaluate efficacy and safety of inhaled CsA in improving BOS-free survival following lung
aAt the time of scintigraphic study.
180 CORCORAN ET AL.
mass was 2.31lm with a GSD of 2.00. Calculations based on
radioactivity yielded MMAD of 2.44lm with a GSD of 1.73.
Laser diffraction instrument measurements of aerosol size
yielded an average VMD measurement of 2.3lm with a GSD
All enrolled subjects completed both the scintigraphic and
pharmacokinetic aspects of the study. The scintigraphy re-
sults are summarized in Table 3. The average run time of
dosing (including stoppages) was 26.2–6.7min. One patient
(#3) required multiple stoppages due to cough, resulting in a
total run time of 45min. Dosing in patient #9 was adversely
affected due to excessive salivation, resulting in precipitation
of drug within the nebulizer reservoir. For this case, output
as assessed by scintigraphy was approximately half of ex-
pected, although under such circumstances scintigraphy may
not provide an accurate depiction of drug dose. The overall
output from the delivery system was quite consistent, aver-
aging 214.7–35.2mg of CsA, in spite of patient #9, whereas
the average inhaled and deposited dose (total body dose)
was 53.7–12.7mg across the subject group. Pulmonary de-
position averaged 31.8–16.3mg, and stomach deposition
averaged 15.5–11.1mg. The average C/P ratio in the group
was 1.24–0.68. There was no significant change in lung dose
due to predose coaching [34.3–16.7mg coached (#6–10) vs.
29.3–17.4mg uncoached (#1–5)] or in the C/P (1.19 vs. 1.27),
but there was a significant drop in stomach levels (8.3–5.2
vs. 22.6–11.2mg, p=0.03 by t test), suggesting that instruc-
tion may influence the dosing outcome (stomach+mouth,
10.4–5.6 vs. 24.6–12.1mg, p=0.04). Figure 3 includes rep-
resentative images from the deposition scintigraphy studies.
The CsA blood concentration versus time profiles indicate
that a significant amount of CsA is absorbed rapidly with
little time lag (Fig. 4), and peak levels drop below what
would be considered systemically therapeutic within ap-
proximately an hour. Detectable levels in the circulation are
present after 24hr. The pharmacokinetic data for all patients
are summarized in Table 4.
Correlations between deposited doses, pulmonary func-
tion, and pharmacokinetic values are reported in Table 5.
Deposited lung dose increased with lung capacity [forced
vital capacity (FVC)] (p=0.02). Central lung dose and C/P
ratio increased with FEV1%p [the percentage of predicted
forced expiratory volume in 1sec] (p=0.05, 0.01). The
correlation between total deposited dose and AUC(0–24)
approaches significance (p=0.06).
The primary goal of the study was to define the phar-
macokinetics of CIS. The secondary goal was to measure the
total and regional deposition of CIS. Total CsA deposition
here averaged 53.7mg, and lung dose averaged 31.8mg.
These doses are higher than previously reported doses from
other devices. Total dose is increased by 80% and 36%
compared with doses found by Burckart et al.(12)and Cor-
coran et al.,(13)respectively. Pulmonary dose is increased by
18% and 6%, respectively.
Successful deposition of drug in the small airways is likely
necessary to suppress chronic lung transplant rejection,
which manifests as bronchiolitis obliterans, a fibrous ob-
struction of the membranous and respiratory bronchioles.(14)
These airways are large in number (>4,000) and small in
diameter (*1mm).(15,16)Little knowledge exists on how to
successfully target this zone; however, smaller aerosols are
more likely to penetrate beyond large airways(17)and
breathing maneuvers(18)may offer some utility. The MMAD
of the CIS aerosol was 2.3lm, which is somewhat smaller
NGI studies. Radioactivity is compared with drug mass
within each aerosol size range after the nebulization of CsA
solution for inhalation with a small amount of added Tc-
DTPA. Results are means–SD.
Comparing radioactivity and drug dose through
drug mass and radioactivity associated with Tc-DTPA. The
correlation between radioactivity and drug mass provides
the basis for the performance of deposition scintigraphy
studies. Results are means–SD.
Demonstrating the linear relationship between CsA
NEBULIZED CYCLOSPORINE IN LUNG TRANSPLANT PATIENTS 181
than that of most aqueous aerosols generated by jet nebu-
lizers and is likely a reflection of the physicochemical char-
acteristics of the propylene glycol vehicle and the high
operating pressure used to generate the aerosol (30 psig).
Overall, 10.6% of the nebulizer fill dose (14.8% of the emitted
dose) was deposited in the lungs—values typical for jet
Deposited lung dose increased with FVC, indicating that
higher lung doses are associated with larger lung volumes,
likely due to increased total drug exposure. Previous studies
have indicated an inverse relationship between FEV1 and
central lung deposition.(21)Here we see the opposite effect as
central dosing increases with FEV1%p. In previous studies,
decreased FEV1 was likely associated with large airway
obstruction. Here it may simply indicate respiratory ability.
Associations specifically with central lung dosing could be
related to increased inhalation flow rates, or could be coin-
cidence. Weak trends between both FEV1%p and FEV1 and
lung dose are apparent when the data are examined care-
fully, and may indicate better dosing in healthier lungs.
Observations of oropharyngeal deposition and swallow-
ing during early imaging studies prompted an enhancement
to the procedure midway through the study. The first five
patients who were evaluated were given no additional in-
struction beyond what was provided during the initial dose
titration phase of CYCLIST. For the last five patients, the
instructions for use were verbally reinforced immediately
before dosing commenced. The outcome of these efforts was
an observed drop in stomach deposition, indicating that
improved breathing technique was indeed reducing oro-
pharyngeal deposition. However, there were no statistically
significant changes in total, pulmonary, or peripheral lung
dose, C/P ratio, or AUC as a result of coaching in this small
subject group, but trends toward improved dosing with
coaching were seen.
Beyond coughing and some hoarseness, no other acute
adverse effects were associated with CIS administration.
However, the high initial lung doses do raise the question of
whether the drug and/or vehicle will have a deleterious ef-
fect on lung tissue. In vitro culture studies using human
airway epithelial cells have shown that 10lg/mL concen-
trations of CsA cause increases in the release of lactate de-
hydrogenase and inflammatory cytokines and inhibition of
cell growth.(22)However, the high lung concentrations post
aerosol administration will decline rapidly, unlike those in
cell culture, and aerosol studies carried out in beagle dogs
administered CIS three times per week for 9 months at dose
levels up to 12 times higher per kilogram than those received
Table 3. Dosing Information from Scintigraphy Studies
Inhaled and deposited
aIncludes time for stoppages at subject request during dosing.
bT/E, tracheal-esophageal region.
cC/P, central-to-peripheral lung deposition ratio, average of left and right lungs.
dSingle-lung transplant; left native lung.
Subject with lowest pulmo-
nary dose (13.2mg). (B) Sub-
ject with highest pulmonary
dose (61.3mg). (C) A single-
lung recipient [3.9mg (na-
All images are posterior.
182CORCORAN ET AL.
by human patients, demonstrated no macroscopic or histo-
pathological changes to lung tissue.(23)
The observations of drug reaching the stomach raise the
possibility that oral absorption may contribute to the blood
concentration versus time profiles after inhalation. No char-
coal block was given prior to dosing, and therefore oral
uptake cannot be ruled out. Visually, the profiles suggest
that the impact of oral uptake is small, because peak con-
centrations were found 15–30min post dose and declined
afterwards. If oral absorption was significant, we would
have expected skewed profiles in the 2–4-hr time frame.
Mechanistically, unformulated CsA would be subjected to
acid degradation within the stomach,(24)adding to the ex-
pected drug losses associated with gut wall and hepatic
CsA inhalation is intended as a topical treatment of the
lungs. Limited systemic exposure is desirable, because sys-
temic CsA may contribute to nephrotoxicity and other un-
desirable side effects. In these studies, the average peak
systemic concentration (Cmax) of inhaled CsA was 371.7
ng/mL with an average AUC(0–24) of 1,492.8ng hr/mL.
Burckart et al.(12)reported Cmaxof 206.3–89.6ng/mL and
AUC(0–24) of 1,033.9–344.7ng hr/mL. Previous studies of
oral CsA administration in lung transplant recipients have
reported peak levels of 1,710–482ng/mL, trough levels
of 346–112ng/mL, and AUC(0–12) of 7,447–1,870ng
hr/mL.(26)Total weekly exposure for inhaled CsA (three
times per week) would be 4,479ng hr/mL compared with
weekly (twice per day) exposure of 104,258ng hr/mL with
oral CsA.(26)Thus, aerosol therapy would add only 4% to the
typical cumulative weekly exposure of oral CsA therapy.
In summary, we have performed simultaneous deposition
scintigraphy and pharmacokinetic studies of inhaled CsA in
10 lung transplant recipients participating in the Phase 3
CYCLIST studies. Peak systemic drug levels were similar to
trough levels reported after oral administration, and the total
systemic exposure associated with inhaled administration
was a small fraction of the exposure associated with oral CsA
administration. This study demonstrates the feasibility of
inhaled drug delivery in lung transplant recipients. Although
dosing was somewhat variable, delivery efficiencies typical
for medical nebulizers were attained, and substantial pul-
monary doses were achieved without excessive systemic
The services of the Clinical Translational Research Center
at the University of Pittsburgh were supported by the Na-
tional Institutes of Health through grants UL1 RR024153 and
UL1TR000005. APT Pharmaceuticals funded the perfor-
mance of these studies.
Author Disclosure Statement
T.E.C. and B.A.J. have received research grants from APT
Pharmaceuticals. R.N., W.V., and S.D. are employees of APT
1. Iacono AT, Keenan RJ, Duncan SR, Smaldone GC, Dauber
JH, Paradis IL, Ohori NP, Grgurich WF, Burckart GJ, Zeevi
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lized delivery. Results are means–SD.
Blood concentration versus time profiles of CsA
Table 4. Summary of Pharmacokinetic Data
Cmax, maximum blood concentration; Tmax, time to maximum
concentration; AUC(0–24), area under the concentration vs. time
curve from 0 to 24hr; MRTni, mean residence time (noninstanta-
neous); t1/2, half-life.
Table 5. Correlations between Deposited Dose,
Pulmonary Function, and Pharmacokinetics
FEV1(L) FEV1%p FVC (L) AUC
Total deposited dose (mg)
Lung dose (mg)
Peripheral lung dose (mg)
Central lung dose (mg)
Stomach dose (mg)
p values based on linear regression are reported. Central lung dose
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FEV1%p, percentage of predicted 1-sec forced expiratory volume;
C/P ratio, ratio of central-to-peripheral dose; AUC, area under the
concentration vs. time curve from 0–24hr (ng hr/mL).
NEBULIZED CYCLOSPORINE IN LUNG TRANSPLANT PATIENTS 183
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Received on February 13, 2013
in final form, March 28, 2013
Address correspondence to:
Dr. Tim Corcoran
NW628 UPMC MUH
3459 Fifth Ave.
Pittsburgh, PA 15213
184 CORCORAN ET AL.