Download Prolonged Efficacy Following One Dose of a Novel

F-761
Prolonged Efficacy Following One Dose of a Novel Echinocandin, CD101, in a
Neutropenic Mouse Model of Disseminated Candidiasis
Voon Ong, Ph.D.
Cidara Therapeutics, Inc.
6310 Nancy Ridge Dr., Suite 101
San Diego 92121 USA
[email protected]
V. Ong,1 L. Miesel,2 K. Bartizal,1 H.H. Huang,2 and J.C. Chien2
1Cidara Therapeutics, Inc., San Diego, CA, USA; 2Eurofins Panlabs, Taiwan
ABSTRACT
METHODS
RESULTS (cont’d)
RESULTS (cont’d)
RESULTS (cont’d)
Background: CD101 is a novel echinocandin antifungal with long-acting pharmacokinetics
and chemical stability that is being developed for once-weekly administration. The systemic
candidiasis model with neutropenic mouse was employed to assess the duration of CD101
efficacy over a one week time course.
Minimum inhibitory concentration (MIC). The MIC in a broth
susceptibility test was read at 50% inhibition of growth as defined by
CLSI M27-A2. CD101 and anidulafungin (ANID) were each tested by
2-fold serial dilution from 16 to 0.0156 µg/mL. A 2 µL aliquot of each
dilution was added to 198 µL of RPMI + MOPS with 1-5 x 103 CFU/mL
of C. albicans (R303). The plates were incubated at 35-37C for
48 hrs and then visually scored.
Table 1. Comparative MIC values of CD101 and ANID against
C. albicans (R303) would not suggest that CD101 performs better
than ANID in vivo.
Figure 3. 7-day time-kill in neutropenic mouse C. albicans model
suggests prolonged effect from as low as one dose of 1 mg/kg.
Figure 5. Bar graph format of Figure 4. A >2-log reduction (*) in the
kidney counts of the treatment groups compared to vehicle. The % of
animals with counts below the LOD is in parentheses.
Conclusion: Efficacy of CD101 in the murine model indicates promise for the treatment of
human systemic candidiasis with a once per week dosing regimen.
INTRODUCTION
Figure 1. CD101 was efficacious at single doses of 0.5, 1.5, and
4.5 mg/kg given IP at 24 h after infection, demonstrating dosedependent reductions of kidney burden that were greater than those of
anidulafungin (ANID) at the 0.5 and 1.5 mg/kg doses and similar to
that of ANID at the high dose.1
6
2
1
Anidulafungin
CD101
1
D
C
Compound
Dose-Normalized
Cmax
([µg/mL]/[mg/kg])
Dose-Normalized
AUC0-24
([µg.h/mL]/[mg/kg])
CD101
1 - 16
3.5
33
ANID3,4
5 - 40
1.2
17
45
CD101
40
1 mg/kg IP
35
3 mg/kg IP
30
10 mg/kg IP
25
20
15
Steady State
24
48
72
96
120
144
h
6 r
1 h
4 r
4
1 h
9 r
2
h
r
9
8
4
h
6 r
1 h
4 r
4
1 h
9 r
2
h
r
8
8
C D101,
C D101,
C D101,
C D101,
1 m g /k g
3 m g /k g
1 0 m g /k g
3 0 m g /k g
CD101 displays a concentration-dependent pattern of activity in vivo,
consistent with that observed for other echinocandins.6 Its superior PK
properties suggest that a front-loaded CD101 dosing regimen is an
optimal approach to maximize drug effect early in the course of
therapy when the density of the pathogen is the greatest, providing the
opportunity to increase the rate and extent of pathogen killing and
resistance prevention.
REFERENCES
V e h ic le
C D 1 0 1 , 1 m g /k g , IP
C D 1 0 1 , 3 m g /k g , IP
C D 1 0 1 , 1 0 m g /k g , IP
5
* *
(1 0 0 )(1 0 0 )
CONCLUSIONS
Drug treatment at 24 h post infection
6
*
(1 0 0 )
168
T im e (h )
7
4
4
V e h ic le
C D 1 0 1 , 3 0 m g /k g , IP
1. ICAAC 2015, Poster F-750.
2. ICAAC 2015, Poster A-015.
4
3. Seyedmousavi S, et al. Antimicrob Agents Chemother. 2013;57:303–308.
3
4. Gumbo T, et al. Antimicrob Agents Chemother. 2006;50:3695-3700.
5. ICAAC 2015, Slide Session 044: Pharmacokinetics-Pharmacodynamics
(PK-PD) of a Novel Echinocandin, CD101, in a Neutropenic Murine
Disseminated Candidiasis Model.
2
1
0
10
h
8 r
h
7 r
2
h
r
0
0
*
LO D
2
Figure 4. Even with a delayed treatment start at 24 hrs post-infection
in the same neutropenic mouse C. albicans model, the efficacy was
observed from as low as one dose of 1 mg/kg.
Figure 2. Mouse concentration-time profiles at different IP doses
with terminal half-life >30 hrs; PK-PD analysis from dose
fractionation studies of efficacy in a neutropenic mouse model is
explored in a separate presentation.5
*
( 1 0 0 )( 1 0 0 )
3
0
Doses
(mg/kg)
(4 0 )
2
1
1
* ( 2*0 )
(6 0 )
9
4
* *
4
C D 1 0 1 , 3 0 m g /k g , IP
*
* *
(6 0 )
h
6 r
1 h
4 r
4
1 h
9 r
2
h
r
C D 1 0 1 , 1 0 m g /k g , IP
*
9
5
3
*
8
C D 1 0 1 , 3 m g /k g , IP
* *
4
6
4
h
6 r
1 h
4 r
4
1 h
9 r
2
h
r
C D 1 0 1 , 1 m g /k g , IP
9
V e h ic le
0
24
48
72
96
120
144
168
192
6. Perlin DS. Future Microbiol. 2011;6:441-457.
T im e (h )
5
/k
g
m
.5
4
,
0
1
ID
A
N
1
0
1
D
C
g
g
/k
m
.5
4
,
1
,
,
ID
N
A
g
/k
g
m
.5
.5
1
.5
0
,
1
0
1
D
C
g
g
/k
m
g
m
m
.5
0
,
ID
N
A
g
/k
/k
g
4
2
,
le
ic
h
e
V
g
r
h
r
h
2
,
le
ic
h
e
V
We aim to show that the superior pharmacokinetic properties of
CD101 translates to prolonged efficacy in vivo in a neutropenic mouse
model of disseminated candidiasis.
g
0
0.0078
Table 2. Comparative PK from IP administration of CD101 and ANID
in ICR mouse showing superior pharmacokinetics of CD101 that likely
accounts for better efficacy compared with ANID (given comparable
protein binding of both compounds2).
Plasma Concentration (µg/mL)
L o g ( C F U /g ) in k id n e y
3
7
4
ANID
5
4
0.031
2
CD101
L o g ( C F U /g ) in k id n e y
Neutropenic animal infection model. ICR mice (N=5/group) were
rendered neutropenic by IP injections of cyclophosphamide at
150 mg/kg 4 days before infection (Day –4) and at 100 mg/kg 1 day
before infection (Day –1). On Day 0, animals were inoculated with
C. albicans (R303) intravenously (IV, 0.2 mL/mouse) with the
inoculum size at 103 or 105 CFU depending on study. CD101 doses
(at 1, 3, 10 or 30 mg/kg) were administered IP once at 2 or 24 h after
infection. Animals were euthanized at time points up to 7 days posttreatment followed by CFU enumeration in kidney homogenates.
MIC (µg/mL)
5
Mouse pharmacokinetics. PK of CD101 was evaluated in ICR mice
(N=3/dose) after 1, 4, or 16 mg/kg intraperitoneal (IP) administration.
Plasma was harvested at pre-selected times post-dose and analyzed
by LC-MS/MS.
RESULTS
Echinocandins are potent inhibitors of numerous pathogenic fungal
species, including Candida spp. The primary pharmacodynamics (PD)
of CD101, a novel echinocandin with improved pharmacokinetic (PK)
properties relative to the other agents in the class, has been evaluated
in both in vitro and in vivo studies with a focus on properties that
support the proposed clinical use of once-weekly treatment of
invasive/systemic candidiasis.
Compound
6
L o g ( C F U /g ) in k id n e y
Results: CD101 was significantly efficacious when administered by the IP route across a wide
range of doses and exposures that are projected to be achievable in the clinic (Panel A;
P ≤ 0.005 for the 24 and 72 h time points). Efficacy was observed when dosing was delayed
to 24 h after infection (Panel B; P < 0.005 for the 48 h time point).
Drug treatment at 2 h post infection
L o g ( C F U /g ) in k id n e y
Methods: Neutropenic mice were infected by injection of C. albicans strain R303
suspensions into the tail vein, with an inoculum size of 103 CFU per mouse. Test agent and
vehicle were administered to groups of 5 animals with a single intraperitoneal (IP) injection at
2 h or 24 h after infection. Animals were humanely euthanized at time points up to 7 days
post-treatment then Candida counts were measured in kidney homogenates (CFU/g-tissue).
Unpaired Student’s t test was performed to determine the significance of treatment effects
relative to the vehicle control groups.
0
0
4
8
12
Time (h)
16
20
24
ACKNOWLEDGEMENTS
We thank K. James and R. Krishnan for providing the mouse IP
pharmacokinetics data for CD101.