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Dose Selection in Pharmaceutical
Development
Eliseo Salinas, MD, MSc
Chief Scientific Officer
Shire Pharmaceuticals
Summary
 Context: drivers for dose selection
 Stepwise approach for dose selection
 A case study
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Dose-selection / Definition
Choice of a dose / range of doses supposed to
include the ultimately safe and effective dose /
range of doses.
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Cash flow over the product life cycle
Peak year sales
Market
introduction
Generic entry
Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29
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Cash flow over the product life cycle
Sales
Market
introduction
R&D costs
Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29
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Cash flow over the product life cycle
IP protection
Shift to the left
Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29
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Cash flow over the product life cycle (-3 years)
IP protection
Shorten clinical
development
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Clinical development
phase I
phase II
Healthy volunteers (small n)
-Initial tolerability
-PK
phase III
Patients (small n)
-Initial efficacy
-Initial tolerability
-Initial safety
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DATA?
registration
Drug interactions
Special pharmacology
DATA?
Patients (big n)
-Pivotal efficacy
-Pivotal safety
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Cost and duration of clinical development
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Mean out-of-pocket cost
(millions 2000 dollars)
Mean duration
(months)
Phase I
$15.2M
21.6 mo
Phase II
$23.5M
25.7 mo
Phase IIII
$86.3M
30.5 mo
DiMasi JA et al, Journal of Health Economics 22 (2003), 151-185
9
Drug development across therapy areas
Central Nervous
System
Cardiovascular
Antiinfective
Clinical phase
Approval phase
Analgesic/Anesthetic
0
20
40
60
80
100
120
140
Months
DiMAsi et al, Drug Information Journal, 2004, vol 38, pp 211-223
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Drug development mantra
Start with the end in sight
How will we design our pivotal phase III?
 Duration of treatment?
 Number of doses?
 Need for titration?
 Ideas re dose-response?
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Dose response: the case of antipsychotics
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Davis JM et al, J Clin Psychopharmacol 2004, 24:192-208
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Single ascending dose (SAD) in healthy volunteers
Search for a maximal tolerated dose (MTD)
Dose
Significant AEs
MTD
A
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B
C
D
E X
F
G
H
I
X J
Cohorts
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Tolerability or need for titration:
Multiple Ascending Dose (MAD)
60
50
Dose
40
30
MTD single dose
20
10
0
1 2 3 4 5 6 7 8
Cohort A
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1 2 3 4 5 6 7 8
Cohort B
1 2 3 4 5 6 7 8
Cohort C
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How to select doses for the SAD?
 Toxicology: initial dose in SAD as a fraction (1/10) of No
Adverse Event Level (NOAEL) dose (FDA guidelines)
 Allometric scaling: target concentration in relevant animal
model corrected by total body weight
 Physiologically Based Pharmacokinetic Modelling (PBPK):
modelling of distribution in several tissues and blood
circulation
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Dose response relationships and dose selection
B
Effect
Was true MTD reached?
C
C
A
B
C
B
1
5
C
A
B
A
A
B
C
30
35
40
10
15
20
25
Dose
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A case study: desvenlafaxine succinate (DVS)
 Case study based on public information only
 DVS: active metabolite of venlafaxine (Effexor®)
 Extensive knowledge of animal and human pharmacology of
parent
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Effexor®: pharmacology
 Mechanism of action
 Potent inhibitor reuptake of serotonin and norepinephrine
 Weak inhibitor of dopamine reuptake
 Dosing:
 75 to 375 mg / day
 “… certain patients may respond more to higher doses …”
(Physician’s Desk Reference)
 Dose-dependent effects on blood pressure (PDR)
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DVS pharmacology
 Good affinity for serotonin,
norepinephrine and dopamine
transporters
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Deecher AC et al, The Journal of Pharmacology and Experimental Therapeutics, 2006, 318, 657-665
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DVS pharmacology (cont’d)
 Potent inhibitor of reuptake of
serotonin and norepinephrine
 Weak inhibitor reuptake of
dopamine
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Deecher AC et al, The Journal of Pharmacology and Experimental Therapeutics, 2006, 318, 657-665
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DVS: SAD and MAD findings
 Single Ascending Dose (SAD)
 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, 750 mg, 900 mg / 24h
 n=10 (6 DVS, 2 venER 150, 2 pcb)
 Max tolerated single dose: 750 mg/24h
 Multiple Ascending Dose (MAD)
 300 mg, 450 mg, 600 mg / 24h
 n=12 (9 DVS, 3 pcb)
 Max tolerated multiple dose: 450 mg
[ASCPT abstract PII-122] Clin Pharmacol Ther 2005, 77(2) p82
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[ASCPT abstract PII-130] Clin Pharmacol Ther 2005, 77(2) p84
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Change from baseline
DVS: efficacy results / dose finding study A
*
14
12
-12.6
10
8
-12.1
-9.3
6
4
2
0
HAMD
 18-75 year old patients with depression
Placebo
 N=375
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CGI Improvement score
 8 week
 Fixed doses: 200 mg / 400 mg /
placebo
*
3
2
DVS-200
*
2.7
2.2
DVS-400
*
2.3
1
0
CGI-I
Septien-Velez L et al, Int Clin Psychopharmacol 2007, 22:338-347
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 18-75 year old patients with depression
 8 week
Change from baseline
DVS: efficacy results / dose finding study B
*
12
ns
*
10
-10.6
8
-10.74
-9.63
6
-7.65
4
2
0
HAMD
 Fixed doses: 100 mg / 200 mg / 400 mg /
placebo
Placebo
DVS-100
DVS-200
 N=480
CGI Improvement
3
*
DVS-400
*
*
2.5
2.4
2.5
2.8
2
2.3
1.5
1
0.5
0
CGI-I
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Kaneth J et al, Future Neurology, 2007, 2, 361-371
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Safety in pivotal DVS studies A(1) and B(2)
Placebo
200 mg
400 mg
Placebo
100 mg
200 mg
400 mg
Nausea
14 (11)
57 (46)
63 (50)
10 (8)
41 (35)
36 (31)
47 (41)
Supine pulse rate
-1.43
1.79
5.79
0.15
-0.03
1.06
4.19
Systolic BP
-1.39
0.85
1.19
0.23
2.96
3.62
4.05
Diastolic BP
-1.03
0.91
1.35
0.44
2.21
2.84
3.41
QTc (Bazett)
-0.36
2.53
7.78
NR
4.64
6.66
7.25
(1) Septien-Velez L et al, Int Clin Psychopharmacol 2007, 22:338-347
© Shire
(2) Kaneth J et al, Future Neurology, 2007, 2, 361-371
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DVS: summary of regulatory history
 Dec 22, 2005: Wyeth submits NDA for depression
 Sept 8, 2006: FDA’s Psychopharmacologic Drugs Advisory Committee
to discuss DVS
 Jan 22, 2007: FDA issues Approvable letter for DVS (requires low dose
studies)
 August 2007: Wyeth submits complete response to approvable letter
(includes two additional positive depression studies at 50 and 100 mg).
 Feb 29, 2008: FDA Approves DVS for the Treatment of Adult Patients
with Major Depressive Disorder
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Challenges in dose selection for clinical development
 Predictability of animal models
 Pharmacokinetic / pharmacodynamic relationships
 Species-dependent toxicity
 Species-dependent tolerability
 Only a limited number of “shots” to a target in the darkness
 Dose selection remains the most challenging decision in drug
development
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Dose Selection in Pharmaceutical
Development
Eliseo Salinas, MD, MSc
Chief Scientific Officer
Shire Pharmaceuticals