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Pharmacology-Guided Dose-Escalation
of First-in-Class Drugs
almorexant (ORX1/2-antagonist) and rimonabant (CB1-antagonist)
Joop van Gerven, MD, PhD
professor of clinical neuropsychopharmacology, Leiden University
director CNS research, Centre for Human Drug Research
Contents:
• causes of failed development
• getting the pharmacology right for highly
selective innovative drugs
Failed Clinical Trials in Phase II/III
Phase II
Phase III
Arrowsmith J. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Disc 2011:10:328-9
Arrowsmith J. Trial watch: Phase III and submission failures: Nat Rev Drug Disc 2011:10:82.
Determinants of Drug Efficacy
variability
pharmacology
etiology
Cohen AF. Developing drug prototypes: pharmacology replaces
safety and tolerability? Nat Rev Drug Discov. 2010;9:856-65
…25 Drugs Withdrawn After Launch…
Drug
amineptine (Survector)
cisapride (Propulsid)
troglitazone (Rezulin)
alosetron (Lotronex)
phenylpropanolamine (Dexatrim)
cerivastatin (Lipobay, Baycol)
rapacuronium (Raplon)
trovafloxacin (Trovan)
levomethadyl
rofecoxib (Vioxx)
pemoline (Cylert)
valdecoxib (Bextra)
natalizumab (Tysabri)
Tc fanolesomab
hydromorphone (Palladone ER)
pergolide (Permax)
tegaserod (Zelnorm)
lumiracoxib (Prexige)
aprotinin (Trasylol)
rimonabant (Acomplia)
efalizumab (Raptiva)
sibutramine
gemtuzumab ozogamicin (Mylotarg)
drotrecogin alfa (Xigris)
Approved
1978
1993
1999
2000
1970's
1997
1999
1998
1993
1999
1975
2004
2004
2004
2004
1988
2004
2006
1993
2006
2003
1988
2000
2001
Withdrawn License
2000
2000
2000
2000
2000
2001
2001
2001
2003
2004
2005
2005
2005
2005
2005
2007
2007
2008
2008
2008
2009
2010
2010
2011
pharmacological effect/predictable at time of registration
pharmacological effect/predictable after time of registration
drug-class specific rare adverse drug reaction
rare idiosyncratic/allergic adverse drug reaction
Reason
22
7
1
1
30
4
2
3
10
5
30
1
1
1
1
19
3
2
15
2
6
22
10
10
abuse, acne
cardiac arrythmia
liver failure
ischemic colitis
haemorrhagic stroke
rhabdomyolysis
bronchospasm
liver failure
abuse, cardiac arrythmia
cardiac risk
liver failure
cardiac risk
leucoencephalopathy
allergy
alcohol interaction
valve regurgitation
cardiac risk
liver failure
cardiac risk
depression
leucoencephalopathy
cardiac risk
lack of efficacy
lack of efficacy
27%
9%
36%
36%
⅓ pharmacologic AEs:
-predictable
-dose-related
1980-2000: Dose Reductions After Launch
• 27% of all new FDA-registrations of CNS-active drugs
• 79% safety-related
• three times more often in ’95-’99 than in ’80-’85
Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. Postmarketing drug dosage changes of 499
FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf 2002;11:439-46
Optimizing Drug Action:
getting the pharmacology right
Traditional – tolerated dose
T
E
Use traditional approach for modern drugs
T
E
Pharmacology-Based Phase I
T
E
P
pharmacological effects:
essential for therapeutic action
PD-effect 1
M-o-A
PD-effect 2
R
PD-effect 4
-clinical effect
-type A adverse effects
-therapeutic range
PD-effect 3
Which Binding Level Is Required for
Therapeutic Activity?
Drug Class
Pharmacological Activity
Receptor Occupancy
Antipsychotic
DA2 competitive
antagonist
- 60-80%
- 17-67% for clozapine
Anxiolytics
GABA-A positive allosteric
modulator
- 5-30% for benzodiazepines
- >60 for new partial subtype
selective compounds
Antidepressant
5HT transporter inhibitor
- 50->80%
CNS stimulants
DA transporter inhibitor
- 50-80%
New compound
New mechanism
- often no availaible tracer
- usually unknown occupancy
Talbot PS, Laruelle M. T he role of in vivo molecular imaging with PET and SPECT in the elucidation of
psychiatric drug action and new drug development. European Neuropsychopharmacology 12 (2002) 503–511
Optimizing Drug Action:
pharmacology-guided dose selection
for first-in-class CNS-active drugs
Case 1: dual-orexin antagonist
almorexant
Case 2: cannabinoid CB1 antagonists
surinabant and rimonabant
Pharmacology-Guided Dose Selection - Case 1:
Almorexant –first Dual ORX1/2-Antagonist (DORA)
• first-in-class with theoretical
narcolepsy-like AEs:
VAS alertness
VAS external perception
–
–
–
–
sleep attacks
cataplexy
hypnagogic hallucinations
sleep paralysis
• SAD: extensive CNS-profiling
adaptive tracking
body sway
–
–
–
–
alertness
motor control
psychomimetic effects
sleep EEG
• benchmarking with zolpidem 10mg
sleep EEG δ-power
– (adverse) effect profile
– indications of sleep promotion
Hoever P, De Haas S, Winkler J, Schoemaker RC, Chiossi E, Van Gerven J, Dingemanse J. Orexin receptor antagonism, a new
sleep-promoting paradigm: First-in-humans study with almorexant. CPT 2010;87:593-600
Case 1: PK/PD-based dose selection of almorexant

5 mg zolpidem
Case 1: confirmation of safe effective low dose
• sleep-promotion
• low pharmacological activity
• no harmful narcolepsy-like effects
Hoever P et al. Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. CPT 2012;91:975-85
9351
four
Pharmacology-Guided Dose Selection – Case 2:
rational development of CB1-antagonists
• no PD-effects in healthy subjects
• develop THC-challenge model
• determine peripheral/central
pharmacological activity using PK/PD
• determine relevant inhibition levels in
clinical trials
isolation of THC for inhalation
VAS Alertness
T HC (ng/mL)
VAS Alertness Paper (mm)
80
200
70
60
50
40
30
20
-120
100
0
120
240
Time (min)
360
480
600
120
240
360
480
600
50
0
-5 0
0
120
T HC
240
360
480
Heart Rate
600
T i m e (m i n )
Pl a c e b o
100
60
50
Heart rate (bpm)
Psychedelic VAS 11 (mm)
70
0
100
VAS ‘Feeling high’
80
0
Body Sway
150
Body sway (mm) change from basel i ne
90
300
40
30
20
10
90
80
70
60
0
-10
T i m e (m i n )
-120
0
120
240
Time (min)
360
480
600
50
0
120
240
360
480
600
T i m e (m i n )
T HC
Pl a c e b o
development of THC challenge and PK/PD-model
Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans.
Br J Clin Pharmacol. 2013;76:65-77
Pharmacologically active doses of surinabant: peripheral effects
up to 40% peripheral suppression
100
Observed SR
Population SR 0 mg
Mean (SD) HR (bpm)
90
HR reduction rate (%)
Population SR 5 mg
Population SR 20 mg
Population SR 60 mg
80
70
60mg SD  10mg MD
20mg SD  5mg MD
5 mg SD  2.5mg MD
60
-1
0
1
2
3
4
5
6
7
8
9
10
Time from surinabant dose (h)
SD dose (mg )
dose-dependent suppression of THC-effects
PK/PD-analysis
Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans.
Br J Clin Pharmacol. 2013;76:65-77
Ferrona G, Klumpers L, Van Gerven J, Roy C. PK and PK/PD modeling of CB1 blocker antagonism of THC induced CNS and Heart Rate
effects. PAGE Poster 2010
Pharmacologically active doses of surinabant: central effects
60% central suppression
VAS high reduction rate (%)
VAS F e e l i n g h i g h (mm)
100
80
60
40
60mg SD  10mg MD
20
0
-9 0
-3 0
30
90
150
210
270
330
390
450
510
570
T i m e (m i n )
SD dose (mg )
dose-dependent suppression of THC-effects
PK/PD-analysis
Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans.
Br J Clin Pharmacol. 2013;76:65-77
Guan Z, Klumpers LE, Oyetayo B, Heuberger J, Van Gerven JMA, Stevens J, Freijer JI. Pharmacokinetic/ pharmacodynamic modelling and
simulation of the effects of different CB1 antagonists on ∆9-tetrahydrocannabinol challenge tests in healthy volunteers. (submitted)
we i g h t ch a n g e d u ri n g smo ki n g ce ssa ti o n (kg )
Phase IIa clinical trail: weight gain during smoking cessation
CB1-inhibition 10%
20%
40%
40%
1.50
1.00
0.50
0.00
placebo
2. 5 m g
5 mg
surinabant (all treated)
10 m g
r im onabant 20 m g
(ceased smokers)
•Tonstad S, Aubin HJ. Efficacy of a dose range of surinabant, a cannabinoid receptor blocker, for smoking cessation:
a randomized controlled clinical trial. J Psychopharmacol 2012;26:1003-9
•Rigotti NA, Gonzales D, Dale LC, Lawrence D, Chang Y; CIRRUS Study Group. A randomized controlled trial of adding the
nicotine patch to rimonabant for smoking cessation: efficacy, safety and weight gain. Addiction 2009;104:266-76
CB1-inhibition of clinically active rimonabant dose:
central (60%) > peripheral (40%) suppression rates
60mg SD  20mg MD
60mg SD  20mg MD
5mg SD  5mg MD
weight reduction?
<
psychiatric adverse effects?
Peripherally restrictive CB1-antagonists:
improved therapeutic window?
drinabant
40% peripheral → 30% central suppression
weight reduction?
TM38837
40% peripheral → 15% central suppression
>>
psychiatric adverse effects?
Conclusions
• For selective drugs, pharmacodynamically active
concentrations in healthy subjects are often closely
related to therapeutic levels
• Pharmacokinetic-pharmacodynamic relationships are an
important aspect of ‘proof-of-pharmacology’
• Pharmacology-guided dose escalation
- allows maximization of therapeutic window
- may avoid adverse events associated with
unnecessarily high doses
- increases confidence in dose optimization
Clinical Pharmacology in Clinical Trial Design
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