Pharmacokinetic Evaluation of Liposomal Amikacin for

Pharmacokinetic Evaluation of Liposomal Amikacin for Inhalation in Patients with
Treatment-Refractory Nontuberculous Mycobacteria Lung Infection
Poster #: A-012
Institute For Clinical
Pharmacodynamics, Inc. (ICPD)
(518) 641-6404
crubino@icpd.com
Christopher M. Rubino1, Kenneth N. Olivier2, David E. Griffith3, Gina Eagle4, John P. McGinnis II4, Liza Micioni4, and Kevin L. Winthrop5
Institute for Clinical Pharmacodynamics, Latham, NY, USA. 2National Heart, Lung, and Blood Institute / National Institutes of Health, Bethesda, MD, USA. 3The University of Texas Health Science Center at Tyler, Tyler, TX, USA. 4Insmed Incorporated, Bridgewater, NJ, USA. 5Oregon Health & Science University, Portland, OR, USA.
Conclusions: Amikacin disposition after LAI administration was successfully characterized by population PK. Amikacin
had low systemic bioavailability and minimal systemic exposure compared with published reports for intravenous
amikacin administration.
INTRODUCTION
• Nontuberculous mycobacteria (NTM) lung disease is a serious disease that affects a select group of patients. NTM
lung infections are typically due to Mycobacterium avium complex (MAC); Mycobacterium kansasii; or rapidly
growing mycobacteria such as Mycobacterium abscessus, Micobacterium chelonae, and Mycobacterium fortuitum.1
• Historically, MAC lung infections were typically observed in older male smokers with emphysema. However, an
increase has been observed in the incidence of reported MAC cases characterized by progressive parenchymal
involvement in thin, middle-aged and elderly women with no smoking history or underlying lung disease.2
• Treatment options for NTM lung infection, while limited, involve the use of multidrug antibiotic regimens, including
systemic amikacin for severe or cavitary disease sometimes requiring doses up to 25 mg/kg three times weekly for 2
to 3 months.3,4
• Liposomal amikacin for inhalation (LAI) is being studied as a sustained-release, targeted formulation of amikacin
encapsulated inside nanoscale liposomal carriers designed for administration via inhalation.5-7
• Given the goal of increasing drug exposure within the airway at the site of infection, LAI may be a promising
therapeutic alternative for patients with NTM lung infections.
STUDY OBJECTIVES
• The primary objective was to estimate amikacin systemic exposure after LAI administration using a population
pharmacokinetic (PK) model to describe amikacin disposition in serum and urine.
METHODS
Study Design:
• Data were obtained from a subgroup of patients enrolled in a phase 2, randomized, placebo-controlled study assessing
LAI efficacy and safety in patients with treatment-refractory NTM lung infections (TR02-112).
• Primary efficacy variable was the change from baseline on the full semi-quantitative scale for mycobacterial culture
at Day 84.
Eligibility Criteria:
• Subjects with MAC and/or M. abscessus lung infection with persistently positive mycobacterial cultures while
adhering to standard, guideline-based treatment regimens for at least 6 months were enrolled.
• Eligible subjects were stratified based on the presence or absence of cystic fibrosis (CF) and M. avium vs.
M. abscessus lung disease.
Endpoints:
• For PK analyses, serum and sputum samples were collected pre- and post-dose on Days 1, 2, 28, 56, 84, 112, and 168;
urine samples were collected post-dose on Days 1, 84, and 168.
Study Assessments:
• Maximum serum concentration (Cmax) of amikacin and area under the concentration-time curve at 24 hours (AUC24)
on Day 1 and at steady state were calculated from individual fitted profiles.
Treatments:
• Patients received LAI 590 mg once daily or placebo via a customized investigational eFlow technology nebulizer
(PARI Pharma GmbH) added to their ongoing stable multidrug regimen for 84 days followed by up to 84 days of
open-label add-on LAI 590 mg once-daily treatment.
®
Population PK Analysis Methods:
• All data preparation was performed using a qualified installation of SAS Version 9.4 software (SAS Institute, Inc.,
Cary, NC).
• Steps were taken to ensure that accurate datasets were constructed for the PK analyses, including exclusions of
statistically significant outlier concentrations. Serum concentrations that were below the limit of quantification (BLQ)
were flagged and included in the analysis if an assay estimated value was reported. If an assay estimated value was
not reported and if the serum concentration was obtained prior to the first dose, the value was excluded from the
analysis. For serum concentrations observed after the first dose and flagged as BLQ, the population analysis program
(S-ADAPT 1.57) fit the BLQ value using the Beal M3 method.8
• A total of 16 females were randomized to LAI and provided blood and/or sputum samples for the determination
of amikacin concentrations while on active treatment. Median (range) age was 57 (20-77) years; body weight
was 65.2 (43.9-80) kg (Table 1).
• Ultimately, a total of 111 serum concentrations from the 14 patients were available for the PK analysis. A total of
16 of the 111 post-dose serum concentrations were BLQ and identified as such in the dataset. A total of 23 urine
samples from 14 patients were available for the PK analysis, none of which were BLQ. Despite the number of
samples obtained, they were spread over up to 6 occasions, resulting in a sparse overall sampling scheme.
• Scatterplots of the serum concentration data vs. time since the last dose for TR02-112 are provided in Figure 1.
Consistent with the sampling scheme described in the study protocol, the samples were clustered within two
primary windows: 0 to 4 hours and 12 to 24 hours after the dose. Some samples were drawn at >24 hours after
the previous dose, which likely reflects the timing of the at-home doses relative to the time of clinic visits at
which PK samples were drawn. As expected given the route of administration, considerable variability was seen
in the observed amikacin concentrations over time.
• The population PK model from the pooled CF PK analysis provided an adequate fit to the data from TR02-112
alone. Given that samples were drawn on up to 6 different occasions in a given patient, and as few as one sample
was drawn on some occasions, random inter-occasion variability was not estimated for any of the PK parameters.
• The population PK parameter estimates and associated precision from the final population PK model are
provided in Table 2. Despite the sparseness of the sampling scheme, the fit of the model was robust and
precision of the PK parameter estimates was relatively high. As shown in Figures 2 and 3, the r2 for the
observed versus individual fitted serum concentrations was 0.909 and the r2 for the observed vs. fitted urine
amounts was 0.898. The fit based on the population fitted parameters (right panels of Figures 2 and 3) was less
robust, which is expected given the large amount of inter-individual variability in the absorption of LAI.
• Summary statistics for the amikacin serum exposure estimates on Day 1 and at steady state are provided in Table 3.
–– Clearance is somewhat slower in these patients with NTM lung infections than had been observed in
previous studies of patients with CF and bronchiectasis.9,10 The population mean estimate for the apparent
total serum clearance (CLt/F) was 34.2 L/h in the present study compared with values ranging from 58.8 L/h
in patients with non-CF bronchiectasis to 70 L/h in patients with CF. The population mean renal clearance of
parent drug (CLr) was 37.7 mL/min (2.26 L/h) in the present analysis compared with 45.5 and 43.0 mL/min
in patients with non-CF bronchiectasis and patients with CF, respectively. This lower clearance translates
into slightly higher predicted exposures in these patients with NTM lung infections. The median steady state
AUC24 in the 14 patients in this study was 17.9 mg•hr/L compared with ≈6 mg•hr/L to 12 mg•hr/L in patients
with bronchiectasis and 7 mg•hr/L to 18 mg•hr/L in patients with CF.
–– When compared with the AUC24 of 235 mg•hr/L at steady-state reported for 12 patients with CF given
intravenous (IV) amikacin 30 mg/kg once daily,11 the mean AUC24 estimates in the NTM patients from this
study (17.9 and 21.3 mg•hr/L on Day 1 and at steady-state, respectively) indicate that the lower systemic
bioavailability and lower administered dose of amikacin after LAI administration to patients with NTM lung
infections remains sufficiently low to result in minimal systemic exposure. For the proposed clinical dose of
590 mg of LAI once daily, the mean daily AUC observed for the above-described 12 patients with CF who
received amikacin 30 mg/kg IV once daily was ≈13 times higher than the median estimated AUC in patients
enrolled in TR02-112.
–– The exposures in these NTM patients were also much lower than those observed in a large study comparing
traditional amikacin dosing (15 mg/kg/day q12h) to once daily administration (15 mg/kg/day q24h) in
patients with systemic gram-negative infections.12 The mean Cmax estimates in the once-daily and twice-daily
groups (n = 316) were 40.9 and 24.4 mg/L, respectively, 10-20 times higher than the Cmax observed in the
current study (Table 3). In fact, the mean steady-state Cmax in the current study of LAI in patients with
NTM (2.01 mg/L) is lower than the mean trough concentration in the patients treated with IV amikacin
twice-daily (3.1 mg/L) and only slightly higher than the mean trough concentration in the patients treated
with IV amikacin once-daily (1.8 mg/L).12
• Summary statistics for the percentage of LAI dose excreted in the urine, stratified by study day and for all days
combined, are provided in Table 4. On average, ≈7% of the dose administered was excreted in the urine over
a dosing interval (≈24 hours). The range of values observed may be due to the combination of the variability
inherent in the absorption of amikacin from the lung and the error inherent in collecting 24 hour urine samples
in a Phase 2 trial.
Table 1. Summary Statistics of the Baseline Demographics for the Analysis Population
Mean (CV%)
55.8 (27.9)
Median
57
Min
20
Max
77
Actual body weight (kg)
63 (17.2)
65.2
43.9
80
Height (cm)
165 (4.7)
165
149
182
BMI (kg/m2)
23.2 (15.7)
21.6
18.6
29.3
Ideal body weight (kg)
56.5 (12.4)
57.1
42.4
72.3
BSA (m )
1.69 (9.45)
1.75
1.35
Creatinine clearance (mL/min/1.73m2)
87.7 (21.4)
86.3
63.3
2
BMI, body mass index; BSA, body surface area; CV, coefficient of variation.
2
2.0
1.0
0.8
0.6
0.4
0.2
100
50
0
0
0
4
8
12
16
20
Time Since Previous Dose (h)
24
28
0
4
8
12
16
20
24
Note. One below the limit of quantification concentration, observed at >500 hours after the previous dose, is excluded from the
above figures. It was retained in the population pharmacokinetic dataset but does not impact the model fit.
Table 2. Population PK Parameter Estimates and the Associated Standard Errors of the
Mean (SEM) for Amikacin
Population mean
Max
Day 1
6
4.46 (54.8)
3.25
2.71
8.95
Inter-individual variability
(%CV)
Day 84
6
7.74 (77.5)
6.88
1.55
17.2
Day 168
11
8.85 (70.3)
8.42
0.72
22.6
All
23
7.42 (74.6)
5.64
0.72
22.6
CLt/F (L/h)
34.16
26.24
82.73
46.33
Vc/F (L)
339.9
23.29
73.62
45.20
ka (h-1)
1.666
27.09
41.72
74.07
CLr (L/h)
2.260
—
35.28
68.18
CLr coefficient (L/h)
1.949
22.83
CLr WTKG power
0.75
—
Residual error for serum
0.4170
8.161
Residual error for urine
13.02
19.63
• The systemic bioavailability of LAI is sufficiently low to result in minimal systemic exposure relative to
published data on IV administration of amikacin. The PK analysis from this study showed that in patients with
pulmonary NTM disease, peak systemic exposure (Cmax) to amikacin after inhaled administration of LAI can be
up to 10-20 times lower than the exposure reported in other patients given IV amikacin.
Population mean CLr = 1.984∙(WTKG/51)0.75.
Figure 2. Goodness-of-fit plots for the pooled population pharmacokinetic model, serum concentrations
6
2
4
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Obs. = 0.183 + 1.1 · Fitted, r2 = 0.29
6
CONCLUSIONS
• Amikacin clearance was slower and PK exposure was slightly higher in these patients with NTM lung infections
relative to previous reports of amikacin PK after LAI administration in patients with CF or bronchiectasis.
CLt/F, apparent total serum clearance (L/h); CLr, renal clearance of parent drug (L/h); ka, first-order rate of drug absorption;
Vc/F, apparent volume of distribution of the central compartment (L); WTKG, body weight (kg).
0
CV, coefficient of variation.
• Amikacin disposition after LAI administration was successfully characterized by population PK. Amikacin
serum concentrations and urine amounts over time were best described using a three-compartment model with
linear clearance and renal clearance dependent on body weight.
Minimum value of the objective function = 83.37
solid is line of best fit; dotted is line of identity
Table 4. Summary Statistics of the Percentage of LAI Dose Excreted in the Urine Over a
Dosing Interval, Stratified by Study Day and for All Days Combined
Min
%SEM
0
Population Fitted Amikacin Urine Amount (mg)
Median
Final estimate
2
100
Mean (CV%)
%SEM
4
50
N
Final estimate
6
solid is line of best fit; dotted is line of identity
Day
Parameter
Obs. = -0.074 + 1.04 · Fitted, r2= 0.909
50
0
Individual Fitted Amikacin Urine Amount (mg)
28
Time Since Previous Dose (h)
100
50
100
0
solid is line of best fit; dotted is line of identity
0
0.1
Individual Fitted Amikacin Serum Conc (mg/L)
Pharmacokinetic Population
(n = 14)
Variable
Age (y)
4.0
•1
•2
•28
•56
•84
•112
•168
Obs. = 62.3 + -0.472 · Fitted, r2 = 0.00612
Observed Amikacin Urine Amount (mg)
RESULTS
Obs. = -5.69 + 1.09 · Fitted, r2 = 0.898
Observed Amikacin Urine Amount (mg)
Results: PK analysis included 14 females. Median (range) age was 57 (20-77) y; body weight was 65.2 (43.9-80) kg. 111
serum and 23 urine samples from 14 patients, and 143 sputum samples from 12 patients were available for PK analysis.
Median Cmax was 1.59 (0.51-5.49) μg/mL at steady-state and 1.15 (0.43-5.54) μg/mL on Day 1. Median AUC24 was slightly
(19.0%) higher at steady-state than on Day 1 (15.0 [3.75-42.6] vs 17.5 [4.30-54.2] μg∙hr/mL). (Data updated January 13, 2015.)
On average, ≈7% of administered dose was excreted in urine over a dosing interval (≈24 h). Median amikacin levels in
sputum were lower predose (38.2 [0.780-7080] μg/mL) vs. postdose (3185 [1.07-16,799] μg/mL).
Study Day
4
Figure 3. Goodness-of-fit plots for the pooled population pharmacokinetic model, urine amounts
6.0
Amikacin Serum Concentration (mg/L)
Methods: Data were from a subgroup of patients enrolled in a phase 2, randomized study assessing LAI efficacy and
safety in patients with treatment-refractory NTM lung infections. Patients received LAI 590 mg QD or placebo via
nebulizer added to their ongoing stable multidrug regimen for 84 days followed by up to 84 days of open-label LAI 590
mg QD treatment. For PK analyses, serum and sputum samples were collected pre- and postdose on Days 1, 2, 28, 56, 84,
112, and 168; urine samples were collected postdose on Days 1, 84, and 168. Candidate models were fit simultaneously
to serum and urine data using Monte Carlo parametric expectation maximization (S ADAPT 1.57 software). Serum
amikacin Cmax and AUC24 on Day 1 and at steady-state were calculated from individual fitted profiles.
• The structure of the PK model was not modified from the pooled data from previous studies in patients with CF due
to the sparseness of the PK sampling.9 The model was a three-compartment population PK model (one absorption site
[the lung], one central compartment, and one urine compartment) with zero-order drug input into the lungs, a firstorder process from lungs to the central compartment, and linear elimination from the body. Amikacin in the urine was
modeled as accumulating in a urine compartment after clearance from the central compartment (by a first-order renal
process). The urine compartment was modeled as being emptied at the end of the collection intervals.
6
Observed Amikacin Serum Conc (mg/L)
Background: Management of NTM lung infections is limited by lack of effective treatment options. LAI is a novel
amikacin formulation in development for the treatment of NTM lung infections. Amikacin systemic exposure after LAI
administration was characterized by a population PK model to describe amikacin disposition in serum and urine.
Figure 1. Linear (left panel) and log-linear (right panel) scatterplots of serum concentration vs. time since
last dose, colored by study day
Amikacin Serum Concentration (mg/L)
ABSTRACT
• Candidate models were fit simultaneously to serum and urine data using Monte Carlo parametric expectation
maximization (S ADAPT 1.57 software). Interindividual variability was modeled for each PK parameter using either an
exponential variability model assuming log-normal or normal parameter distributions, where appropriate. The presence
of significant inter-occasional variability, for individual population PK parameter estimates, was also assessed. Residual
variability was initially described using an additive error model.
Observed Amikacin Serum Conc (mg/L)
1
4
2
Field SK, Cowie RL. Chest. 2006;129(6):1653-1672.
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Clancy JP, Dupont L, Konstan MW, et al. Thorax. 2013;68(9):818-825.
Rose SJ, Neville ME, Gupta R, Bermudez LE. PLOS One. 2014;9(9):e108703.
Beal SL. J Pharmacokinet Pharmacodyn. 2001;28(5):481-504.
Okusanya OO, Hammel JP, Forrest A, et al. [abstract A1-657] 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA.
September 12-15, 2010.
Okusanya OO, Bhavnani SM, Hammel J, et al. Antimicrob Agents Chemother. 2009;53(9):3847-3854.
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ACKNOWLEDGMENTS
solid is line of best fit; dotted is line of identity
0
0
2
4
6
Population Fitted Amikacin Serum Conc (mg/L)
Conc, concentration.
Table 3. Summary Statistics of the Amikacin Serum Exposure Estimates on Day 1 and at
Steady State Report
Parameter
Mean (CV%)
Median
Min
Max
Cmax, Day 1
1.77 (82.9)
1.15
0.432
5.54
AUC24, Day 1
17.9 (70.5)
15.2
3.82
42.7
1.91
Cmax, steady-state
2.01 (74.2)
1.59
0.510
5.49
140
AUC24, steady-state
21.3 (70)
17.8
4.47
54.3
AUC24, area under the concentration-time curve at 24 hours; Cmax, maximum serum concentration; CV, coefficient of variation.
Poster presented at the 2015 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-21, 2015, San Diego, California.
The authors acknowledge Connexion Healthcare (Newtown, PA) for providing editorial, layout, and design support.
Insmed Incorporated (Bridgewater, NJ) provided funding to Connexion Healthcare for these services. The research
was funded by Insmed Incorporated and supported in part by the intramural research programs of the National
Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung, and Blood Institute (NHLBI),
National Institutes of Health (NIH).
DISCLOSURES
• Christopher M. Rubino is involved in clinical trials sponsored by, and is a consultant of, Insmed Incorporated.
• Kenneth N. Olivier is supported by the Division of Intramural Research of the NHLBI/NIH, and had a
Cooperative Research and Development Agreement between Insmed Incorporated and NIAID/NIH.
• David E. Griffith is involved in clinical trials sponsored by Insmed Incorporated.
• Gina Eagle, John P. McGinnis II, and Liza Micioni are employees of Insmed Incorporated
• Kevin L. Winthrop is involved in clinical trials sponsored by, and is a consultant of, Insmed Incorporated.