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NKTR-061 (Inhaled Amikacin) Achieves High Tracheal Aspirate Concentrations in Intubated, Mechanically Ventilated Patients with
Gram-Negative Pneumonia: A Pharmacokinetic Study
M.S. Niederman1, M. Sanchez2, K. Corkery3, K. Guntupalli4, C.E. Luyt5, J. Chastre5
Winthrop University Hospital, Mineola, NY, USA; 2Hospital Universitario Principe de Asturias, Madrid, Spain; 3Nektar Therapeutics, San Carlos, CA, USA; 4Baylor University Hospital, Houston, TX, USA; 5Hôpital Pitié-Salpétrière, Paris, France
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Abstract
Introduction: The use of intravenous (IV) aminoglycosides is limited by toxicity and poor lung
penetration; aerosol achieves high tracheal aspirate (TA) concentrations.
Objective: Evaluate dose-response to aerosol-delivered amikacin (AMK) and the ability to
deliver 25× reference minimum inhibitory concentration (MIC) value of 256 µg/mL in TA
(6,400 µg/mL).
Patients and Methods: A double-blind, placebo-controlled study of aerosol AMK delivered
via the pulmonary drug delivery system (PDDS®; Nektar Therapeutics) in ventilated patients
with gram-negative pneumonia as an adjunctive to IV therapy, as per American Thoracic
Society (ATS) guidelines. Patients were randomized to receive aerosol containing 400 mg AMK
once-daily (QD) with placebo (ns) 12 h later; 400 mg AMK twice-daily (BID), or placebo BID.
AMK concentration was determined in TA collected 0.25 and 1, 2, 4, 8 and 12 h after morning
dose on day 1 and 3.
Results: AMK 400 mg BID achieved higher TA concentrations than 400 mg QD. Day 3 TA
levels were greater with 400 mg BID (16.2 mg/mL; n=14) than QD (6.9 mg/mL; n=16). Target
levels ≥25× reference MIC of 256 µg/mL were achieved by 74% BID (4/18) vs 40% QD (8/20).
For all patients receiving AMK the TA levels exceeded 1,100 µg/mL or ~4× the reference MIC
target. Clinical cure and bacteriologic eradication rates were similar in all groups. Aerosol AMK
was well tolerated and there was no difference in adverse events across treatment groups.
Conclusion: Delivery of 400 mg of aerosolized AMK BID achieved higher TA concentrations
than QD or placebo. AMK levels exceeded the highest MIC values for pathogens causing
gram-negative pneumonia. The clinical impact of adjunctive aerosol therapy remains to be
determined.
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NKTR-061 delivered directly to the lungs may achieve high tracheal aspirate concentrations and low systemic concentrations thus targeting delivery to the site of infection
while sparing systemic side-effects seen with IV AMK therapy.
A double-blind, placebo-controlled study has been conducted to evaluate the pharmacokinetics, tracheal aspirate concentrations, and safety of NKTR-061 delivery via the
PDDS® in ventilated patients with gram-negative pneumonia, given as adjunctive
antibiotic therapy to IV antibiotics.
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The MIC value used in calculating the target concentration corresponded to that of
organisms expected to be resistant to parenteral AMK therapy. The target TA
concentration was 256 µg/mL (6,400 µg/mL).
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To evaluate NKTR-061 tracheal aspirate concentrations.
Baseline characteristics of patients included in the study are given in Table 1.
Figure 3: Mean (± SD) sputum/tracheal aspirate amikacin concentrations vs time in all treated patients on days 1 and 3.
Materials and Methods
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Baseline parameter
Key inclusion criteria were:
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Men and women >18 years.
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Mechanically ventilated (expected 3 days or longer).
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Clinical diagnosis of:
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VAP (Ventilator-Associated Pneumonia) i.e., pneumonia diagnosed >48 h after
intubation.
HAP (Hospital-Acquired Pneumonia) i.e., pneumonia that occurs 48 h or more
after hospital admission.
HCAP (Health Care-Associated Pneumonia) i.e., pneumonia in patients with a
recent stay in an acute or long-term care facility, including recent dialysis,
chemotherapy or wound care.
Patients (n=69) were randomized to IV antibiotics (monotherapy or combination therapy,
but not IV AMK) plus, either NKTR-061 and/or placebo as follows (Figure 2):
–
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Table 1: Summary of baseline characteristics in a series of 69 patients participating in the study.
NKTR-061 400 mg QD and placebo QD;
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NKTR-061 400 mg BID;
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placebo BID.
IV antibiotics (agent(s) and duration [at least 7 days]) were determined by attending
physician in accordance with the ATS/Infectious Disease Society of America (IDSA)
guidelines.1
Age, years
Mean (SD)
Sex, n (%)
Male
Female
Height, cm
Mean (SD)
Weight, kg
Mean (SD)
APACHE II score,
Mean (SD)
APACHE II score categories,
n (%)
<25
>25
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Figure 2: Study diagram showing randomization of patients and trial flow.
400 mg BID
(n=21)
Placebo
(n=22)
Total
(n=69)
62.8 (15.0)
56.1 (17.6)
62.0 (16.0)
60.5 (16.0)
22 (85)
4 (15)
15 (71)
6 (29)
14 (64)
8 (36)
51 (74)
18 (26)
n
172 (6.9)
169 (9.4)
171 (9.5)
171 (8.6)
n
83.6 (24.8)
69.7 (12.7)
74.6 (12.5)
76.6 (19.0)
16.7 (7.0)
15.7 (4.5)
16.4 (5.2)
16.3 (5.7)
22 (85)
4 (15)
21 (100)
0 (0)
21 (96)
1 (4)
64 (93)
5 (7)
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Day 3 levels >25× reference MIC were achieved by 74% of patients in the BID group, and
40% of patients in the QD group (14/18 vs 8/20 respectively).
At the test-of-cure visit, 93.8% of patients receiving NKTR-061 BID responded to
treatment compared with 87.5% of placebo patients (p=0.467) (Table 3).
At the test-of-cure visit, there was no significant difference in the microbiological
response rate between treatment groups (p>0.999 compared with placebo) (Table 4).
Both doses of NKTR-061 were well tolerated.
Table 3: Clinical cure rate at test-of-cure.
Visit parameter
NKTR-061
400 mg QD (n=20)
NKTR-061
400 mg BID (n=16)
Placebo
(n=19)
Evaluable clinical response at
test-of-cure visit - n
16
16
16
Yes (%)
12 (75)
Overall treatment
p-value
15 (93.8)
14 (87.5)
0.467
Overall treatment
p-value*
Table 4: Microbiological response at test-of-cure.
Higher tracheal aspirate concentrations were achieved with NKTR-061 400mg BID
compared with QD (Table 2).
Table 2: Proportion of patients in each arm who achieved Cmax (tracheal aspirate) ≥25× the reference minimum inhibitory
concentration (256 µg/ml) for hospital-acquired organisms, i.e., 6,400 µg/mL.
400 mg BID
≥6,400
µg/mL
Mean Cmax
Total (%)
Day 1
11,903
µg/mL (n=14)
70%
(14/20)
Day 3:
steady state
16,212
µg/mL (n=14)
74%
(14/19)
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400 mg QD
(n=26)
Results
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Figure 1: Diagram showing the unique pulmonary drug delivery system (PDDS ).
The proportion of patients achieving a target AMK Cmax (maximum concentration
achieved) that was 25× or greater than the MIC for hospital-acquired organisms was
recorded.
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NKTR-061 is a specially formulated preparation of AMK (preservative free, 125 mg/mL)
designed for inhaled administration.
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Tracheal aspirate concentration was collected at 0.25, 1, 2, 4, 8 and 12 h after the
morning dose of study drug on days 1 and 3.
Baseline Demographics
Patients requiring mechanical ventilation are often vulnerable to respiratory infections
such as pneumonia.
NKTR-061 is delivered via Nektar's proprietary PDDS® (Figure 1) to the lungs of patients
who are intubated, and mechanically ventilated, and who have gram-negative
pneumonia.
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NKTR-061 or placebo were to be administered for between 7 days (14 doses) and
14 days (28 doses).
Objective
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Systemic aminoglycosides such as amikacin (AMK) are used intravenously (IV) to treat
intubated patients with gram-negative pneumonia, but their use is limited by high toxicity
and poor penetration into the lung.
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Here we report the results of analyses performed as part of this study, to evaluate the
concentration of amikacin in the TA in patients receiving either NKTR-061 (QD or BID),
or placebo.
Introduction
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400 mg QD
Mean Cmax
6,083 µg/mL
(n=20)
6,893 µg/mL
(n=16)
Total (%)
≥6,400
µg/mL
39%
(9/23)
40%
(8/20)
All patients receiving NKTR-061 had TA levels exceeding 1,100 µg/mL, approximately
4× the MIC target (Figure 3).
On day 3, tracheal aspirate levels were greater with NKTR-061 400 mg BID (16.2 mg/mL,
n=14) than QD (6.9 mg/mL, n=16).
Visit parameter
NKTR-061
400 mg QD (n=20)
NKTR-061
400 mg BID (n=16)
Placebo
(n=19)
Evaluable microbiological
response at test-of-cure visit
-n
16
16
16
Eradication**
11 (68.8%)
11 (68.8%)
10 (62.5%)
>0.999
*The p-value for the overall comparison among the treatment groups is based on a two-sided Fisher's Exact test.
**Eradication rate is the percentage of patients for whom all baseline pathogen(s) were eradicated (as assessed by microbiology results at the test-ofcure visit) or presumed eradicated (i.e. patient was a clinical cure at test-of-cure visit and test-of-cure.)
Conclusions
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NKTR-061 in QD and BID treatment groups was highly concentrated in the TA.
NKTR-061 400 mg twice-daily achieved higher TA concentrations than once-daily or
placebo, and would be an appropriate dose for further investigation into drug efficacy.
Further research is needed to explore the impact of NKTR-061 on nosocomial gramnegative organisms and the clinical efficacy as an adjunct to IV antibiotics in ventilated
patients with pneumonia.
Reference:
1. ATS/IDSA guidelines. Am J Respir Crit Care Med 2005; 171: 388–416.