Transcript Clinical Pharmacology

2008 Post Conference Update:
CHEST
Epidemiology
PAH Registries: Functional Class at Diagnosis
Indicates Delayed Diagnosis
% Patients NYHA Functional Class III-IV at Diagnosis
100
Percent (%)
80
80
72
73
73
REVEAL
REVEAL-TR
REVEAL NIH
75
71
60
40
20
0
N=2967
N=2364 N=1009
PHC
NIH
French
N=578
N=187
N=674
Frost AE. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
Percent (%) Survival
Survival of Geriatric Patients with IPAH
100
90
80
70
60
50
40
30
20
10
0
Expected Survival (NIH)
Actual Survival
Year 1
Year 2
Year 3
Time
N = 20, IPAH patients >65 years.
Uzunpinar A. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.
Prevalence of Resting PH in Patients Referred
for Stress Echocardiography
RSVP >35 mmHg
11.9%
RVSP <35 mmHg
88.1%
N = 2,306 adults referred for stress echocardiography.
Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
Diagnostic and Outcomes Markers
BNP Predictive Value For Adverse Outcomes
644.8
Death
Cardiogenic shock
632.1
Inpatient heart failure
545.6
Outpatient heart failure
472.7
Ventricular dysfunction
424.7
WHO Class IV
BNP (pg/mL)
470.0
WHO Class III
388.4
WHO Class II
151.7
WHO Class I
20.2
Control
12.1
N = 85
Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
Biomarker Predictors of Clinical Worsening In
Bosentan-treated Patients
19.0 *
No Worsening
Clinical Worsening
ET-1 (pg/mL)
12.7
†
138.0
BNP (pg/mL)
85.0
*P = 0.0006. †P = 0.09. Clinical worsening vs no clinical worsening.
Vizza CD. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.
Clinical and Hemodynamic Predictors of
Survival in PAH
NS
P<0.001
Concordance index
(C statistic)
0.8
P<0.005
0.7
0.6
0.5
Age, Sex, WHO Class
Other Clinical factors
ECHO & PFTs
RHC
Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
Doppler Echo Overestimates PAH in Patients
with Scleroderma-related Lung Disease
100
No PH
PH
Percent (%)
80
60
60
40
40
38
25
25
20
0
0
Overestimate PASP
Underestimate PASP
Accurate PASP
Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
PAH in Obese Patients: BMI Correlates With
Worsening Hemodynamics
*
*
70
*
*
60
*
*
*
mmHg
50
40
30
20
*
*
*
*
*
*
10
0
RA Mean
BMI < 25
PA Systolic
PA Diastolic
25≤BMI>30
PA Mean
30≤BMI>35
PCWP Mean
BMI≥35
N = 1600, patients undergoing right heart catheterization for suspected PH.
*p < 0.05 versus comparator.
Kaw R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.
Clinical Pharmacology
No Pharmacokinetic Interactions Between
Ambrisentan and Tadalafil
Cmax
AUC
+5.0%
-12.5%
4-hydroxymethyl +5.8%
ambrisentan
Tadalafil
+0.6%
-14.5%
Ambrisentan
+0.2%
N = 26, healthy volunteers.
Comparison versus single-agent/metabolite.
Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.
Sitaxsentan and Acencoumarol Interactions
3.0
INR
2.5
2.0
1.5
1.0
2
6
10
14
18
22
26
30
34
38
42
46
50
54
58
62
66
70
74
78
82
86
90
94
98
102
106
110
0.5
Duration (weeks)
N = 50. Dose adjustments of 1.6 – 2.0 mg required to reach INR target.
Pulido T, et al. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.
Short-term Clinical Trials
Change in 6-Minute Walking Distance (m)
Tadalafil for PAH: Change in 6MWD at 16 Weeks
placebo
2.5 mg
10 mg
20 mg
40 mg
70
60
50
40
‡
30
†
20
*
10
0
0
4
8
12
Weeks
N = 405
*p = 0.05; †p = 0.03; ‡p = 0.0004 vs. placebo.
Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
16
Tadalafil for PAH: Change in WHO Functional
Class at 16 Weeks
Improved
100%
Percent (%)
15.9
22
No Change
13.8
Worsened
18.3
10.1
45.1
67.1
80%
60%
62.5
63.4
52.4
20.7
25.6
23.8
Placebo
n = 82
2.5 mg
n = 82
10 mg
n = 80
40%
20%
36.6
22.8
0%
20 mg
n = 82
P = NS for all comparisons.
Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
40 mg
n = 79
Long-term Clinical Trials
ARIES-E: Survival With Long-term Ambrisentan
Therapy
100
Survival (%)
80
1 Year = 94%
60
2 Year = 88%
40
ABS
2.5 mg
5 mg
10 mg
20
0
0.0
At Risk:
n=383
0.5
1.0
Years
1.5
n=334
n=315
n=298
Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
2.0
n=255
Change in 6MWD (m)
ARIES-E: Change in 6MWD Over 2 Years With
Ambrisentan
2.5 mg, n = 93
5 mg, n = 186
10 mg, n = 96
70
60
50
40
30
20
10
0
-10
-20
0.0
0.25
0.5
1.0
1.5
Years
Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
2.0
TRIUMPH-1: Long-term Inhaled Treprostinil Plus Oral
Therapy 6MWD Improvements Over Time
Total 6-Minute Walk
Distance (meters)
450
399
400
377
380
383
Month 6
Month 12
Month 18
349
350
300
Baseline
N = 206
Subjects received either bosentan (n = 143) or sildenafil ( n = 63)
in addition to inhaled treprostinil up to 72 µg four times daily
Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
Month 24
Long-term Inhaled Treprostinil Plus Oral Therapy:
Change in NHYA Functional Class Over Time
Change from Baseline
NYHA Unchanged (%)
NYHA Worsened (%)
NYHA Improved (%)
80
70
60
50
40
*
30
20
*
*
*
10
0
Month 3
Month 6
Month 9
Month 12
N=197
N=160
N=121
N=93
*p < 0.05
Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
SUPER-2: Sildenafil Open-label Extension
Clinical Outcomes at 3 Years
100
Percent (%)
80
60
45.8
40
20
17.7
17.3
19.1
Worsened
6MWD
Discontinued/
Lost
Died
0
Improved
6MWD
N = 259
Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
SUPER-2: Long-term Sildenafil Change in
Functional Class at 3 Years
100
Percent (%)
80
60
40
25.6
31
15.2
20
19.1
5.4
3.6
0
Improved
2 Classes
Improved
1 Class
Unchanged
Worsened
1 Class
DC/Lost
N = 259
Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
Died
Long-term Outcomes in Patients Transitioned
From Epoprostenol to SC Treprostinil
NNYA Functional Class Pre- and Post-Transition
(6 months of therapy)
Percentage of Patients (%)
60
50
40
Pre-transition
30
Post-transition
20
10
0
I
II
III
IV
NYHA CLASS
N = 30
Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
Long-term Outcomes in Patients Transitioned
From Epoprostenol to SC Treprostinil
Proportion of Patients
Remaining on SC TRE
Discontinuation of Treprostinil Over Time
(Excluding Death)
1.0
0.8
0.6
0.4
0.2
0
0
12
24
36
Time (Months)
N = 30
Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
48
60
Adverse Effects of PAH Therapies
Epoprostenol-related Thrombocytopenia
450
Platelet count drop >50,000 noted in red
400
350
300
250
200
150
100
50
0
Platelet count
at Baseline
Platelet count at
2-4 months
Platelet count at
8-12 months
Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.
ARIES- 3: Long-term Ambrisentan Following Bosentan
or Sitaxsentan Failure for LFT Abnormalities
Number of Patients
25
20
15
25
(96%)
10
5
1 (4%)
0
No LFT
Abnormalities
ALT/AST
>3X AND 5xULN
N = 226, Subset analysis among 26 patients forced to discontinue alternative ERA
therapy for LFT abnormalities.
Feldman JP. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.
ARIES-1 & 2: 6MWD of Patients Experiencing
Edema Versus No Edema
All
Yes
p = 0.032
60
+34
+39
+19
Change in 6MWD (m)
40
20
0
-20
-40
-9
-1
-60
-80
-100
-55
-120
All
No
Yes
Edema
Placebo
All
No
Yes
Edema
Ambrisentan
Shapiro SL. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
Expanding Populations
PH Inhibits Stress Echo Exercise Duration
100
Ex - PH
Percentage (%) Patients
(7.4±3 mins)
80
No PH
(8.6±3 mins)
60
40
P<0.0001
20
0
2
6
10
14
Exercise duration, mins
Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.
18
PAH in Sickle Cell Disease

10% of sickle cell patients will have PAH/PH
 Pathophysiology not necessarily related to
occlusion
—


Soluble factors have been identified
Mixed PH (PAH combined with diastolic
dysfunction) associated with 11-fold relative risk of
mortality
Clinical trials of PAH medications in sickle cell have
been slow to recruit
Barst RJ, Machado RF, Mubarak KK. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session 15983.
Summary: CHEST 2008

Evidence suggests PAH treatment can be
effective in wide range of patient types and
ages
 Tadalafil may provide a new choice in PDE-5
inhibitor class
 Inhaled treprostinil in combination with oral
therapy may provide an additional choice in
prostacyclin class
 Long-term data for ambrisentan, sildenafil
show 2+ years of benefit in survival and time
to clinical worsening