Pharmacokinetics and Dose
Proportionality of Sublingual Sufentanil
NanoTab in Healthy Volunteers
Pamela P. Palmer, MD PhD
AcelRx Pharmaceuticals, Inc.
October 20, 2009
September 15, 2009
1
Treatment of Acute Pain
 ARX-01:
Sufentanil NanoTab PCA System
Indication: Acute Post-Operative Pain
 Better tolerated than IV PCA morphine
 No IV – improved mobility, fewer complications
 Pre-programmed – reduced risk of errors

 ARX-02:
ARX-01
Sufentanil NanoTab BTP Management System
Indication: Cancer Breakthrough Pain (BTP)
 Timing/PK matches breakthrough episode
 Safer than transmucosal fentanyl

 ARX-03:
Sufentanil/Triazolam NanoTab
Indication: Procedural Analgesia & Sedation
 Rapid onset of sedation and analgesia
 Safe – no monitoring requirement

ARX-02
ARX-03
September 15, 2009
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Sufentanil: A Superior Opioid
 Approved for IV and epidural
administration
 Minimal clinical risk
 High therapeutic index1
 Broad, safe dosing range
 No active metabolites
 Well tolerated
Opioid
Therapeutic Index1
Methadone
12
Meperidine
28
Morphine
70
Hydromorphone
232
Fentanyl
300
Sufentanil
25,000
Therapeutic index = median lethal dose (LD50)/
lowest median effective dose (ED50)
1 De
Castro J: Practical applications and limitations of analgesic anesthesia: a review. Acta Anaesthesiol Belg 1976; 27: 107-28.
September 15, 2009
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NanoTabTM Benefits
 Minimizes saliva production
 Enhanced transmucosal
uptake
 Consistent PK
 High bioavailability
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Low GI uptake = Consistent Tmax
Plasma Levels
Sublingual Sufentanil
NanoTabTM
Tmax 30-90 min
Transmucosal
fentanyl products
Tmax 20-240 min
Therapeutic Window
20
40
60
80
100
Time (min.)
120
140
160
NanoTab Oral Transmucosal Delivery:
Turning Sufentanil AUC on its Side
Sufentanil Plasma Concentration
Single Sublingual Doses vs IV Infusion (over 10 minutes)
90
5 mcg IV infusion over 10 minutes
Serum Concentration (pg/mL)
80
10 mcg
70
5 mcg
2.5 mcg
60
n=12 for each
Mean Tmax= 44 ± 4 minutes
across all sublingual doses
(%CV = 29)
50
40
30
20
10
0
0
20
40
60
80
100
120
September 15, 2009
140
160
180
200
Time (minutes)
6
Sufentanil NanoTabTM 80 mcg Dose
Sufentanil Plasma Concentration in pg/mL (Std Error)
80mcg Single Dose Pharmacokinetics
160.0
140.0
120.0
100.0
80.0
60.0
40.0
20.0
0.0
0
50
100
150
200
250
300
Time (minutes)
ARX-02
80 mcg
Fentora
400 mcg
Actiq
400 mcg
Onsolis
800 mcg
Abstral/Rapinyl**
Active Ingredient
Sufentanil
Fentanyl
Fentanyl
Fentanyl
Fentanyl
Mean Tmax in minutes
53
(30 – 90)
47
(20 - 240)
91*
(35 - 240)
60
(45 – 240)
57***
(22 - 240)
14
(not specified)
(not specified)
(11.5 - 25)
(not specified)
(range)
t1/2 in hours
4.23
11.09
6.43
(range)
(coefficient of variation)
(2.89 – 5.79)
(21%)
(4.63 - 20.59)
(not specified)
(not specified)
(115%)
dose not specified
~20
*Actiq Tmax data was dose adjusted (800 mcg to 400 mcg) per Fentora Package Insert Table 1
**Data (except Tmax, see below) taken from EMEA document describing product characteristics and package labeling http://www.emea.europa.eu/pdfs/human/referral/rapinyl/rapinyl_annexI_IV_en.pdf
***Tmax taken from Lennernas, B. Br J Clin Pharm, 2004. 59:2; 249-253, 400 mcg dose; range from EMEA reference above
September 15, 2009
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Mean (±SD) Cmax of Sufentanil vs. Dose
60
Cmax = 2.31xDose + 1.2
R2 = 0.9852
Cmax, pg/mL
40
j
20
0
0
5
10
15
20
25
Dose, mcg
September 15, 2009
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Mean (±SD) Cmax of Sufentanil vs. Dose
200
Cmax = 1.67xDose + 5.95
R2 = 0.9785
Cmax, pg/mL
150
100
50
0
0
10
20
30
40
50
60
70
80
Dose, mcg
September 15, 2009
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Mean (±SD) AUCinf of Sufentanil vs. Dose
200
AUC = 7.55xDose - 5.0
2
R = 0.9956
AUC, h*pg/mL
150
100
50
0
0
5
10
15
20
25
Dose, mcg
September 15, 2009
10
Mean (±SD) AUCinf of Sufentanil vs. Dose
500
AUC = 5.06xDose + 20.1
R2 = 0.9559
AUC, h*pg/mL
400
300
200
100
0
0
10
20
30
40
50
60
70
80
Dose, mcg
September 15, 2009
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Sublingual Sufentanil NanoTabTM




First transmucosal formulation of sufentanil
Highly consistent Cmax and Tmax – avoids dose stacking
Shorter half-life than fentanyl products – allows more
titratability in the treatment of acute pain episodes
Small NanoTabTM size allows for compact Smart
Dispensers to monitor dosing in both inpatient and
outpatient settings
Thank You
September 15, 2009
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