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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
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.
Failed Clinical Trials in Phase II/III
Phase II Phase III
Determinants of Drug Efficacy
Cohen AF. Developing drug prototypes: pharmacology replaces safety and tolerability? Nat Rev Drug Discov. 2010;9:856-65
etiology pharmacology variability
…25 Drugs Withdrawn After Launch… Drug Approved Withdrawn License Reason
amineptine (Survector) 1978 2000 22 abuse, acne
cisapride (Propulsid) 1993 2000 7 cardiac arrythmia
troglitazone (Rezulin) 1999 2000 1 liver failure
alosetron (Lotronex) 2000 2000 1 ischemic colitis
phenylpropanolamine (Dexatrim) 1970's 2000 30 haemorrhagic stroke
cerivastatin (Lipobay, Baycol) 1997 2001 4 rhabdomyolysis
rapacuronium (Raplon) 1999 2001 2 bronchospasm
trovafloxacin (Trovan) 1998 2001 3 liver failure
levomethadyl 1993 2003 10 abuse, cardiac arrythmia
rofecoxib (Vioxx) 1999 2004 5 cardiac risk
pemoline (Cylert) 1975 2005 30 liver failure
valdecoxib (Bextra) 2004 2005 1 cardiac risk
natalizumab (Tysabri) 2004 2005 1 leucoencephalopathy
Tc fanolesomab 2004 2005 1 allergy
hydromorphone (Palladone ER) 2004 2005 1 alcohol interaction
pergolide (Permax) 1988 2007 19 valve regurgitation
tegaserod (Zelnorm) 2004 2007 3 cardiac risk
lumiracoxib (Prexige) 2006 2008 2 liver failure
aprotinin (Trasylol) 1993 2008 15 cardiac risk
rimonabant (Acomplia) 2006 2008 2 depression
efalizumab (Raptiva) 2003 2009 6 leucoencephalopathy
sibutramine 1988 2010 22 cardiac risk
gemtuzumab ozogamicin (Mylotarg) 2000 2010 10 lack of efficacy
drotrecogin alfa (Xigris) 2001 2011 10 lack of efficacy
pharmacological effect/predictable at time of registration 27%
pharmacological effect/predictable after time of registration 9%
drug-class specific rare adverse drug reaction 36%
rare idiosyncratic/allergic adverse drug reaction 36%
⅓ pharmacologic AEs: -predictable -dose-related
• 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
1980-2000: Dose Reductions After Launch
Optimizing Drug Action: getting the pharmacology right
Traditional – tolerated dose
E
T
Use traditional approach for modern drugs
E
T
Pharmacology-Based Phase I
E
T
P
R
M-o-A
pharmacological effects: essential for therapeutic action
-clinical effect -type A adverse effects -therapeutic range
PD-effect 4 PD-effect 3
PD-effect 2
PD-effect 1
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: – sleep attacks
– cataplexy
– hypnagogic hallucinations
– sleep paralysis
• SAD: extensive CNS-profiling – alertness
– motor control
– psychomimetic effects
– sleep EEG
• benchmarking with zolpidem 10mg – (adverse) effect profile
– indications of sleep promotion
adaptive tracking
sleep EEG δ-power
body sway
VAS alertness VAS external perception
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
four
9351
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
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
0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0
T i m e (m i n )
0
1 0 0
2 0 0
3 0 0
TH
C (
ng/m
L)
0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0
T i m e (m i n )
-5 0
0
5 0
1 0 0
1 5 0
Bod
y sw
ay (
mm
) ch
ange
fro
m b
asel
ine
T HC Pl a c e b oVAS ‘Feeling high’
VAS Alertness Body Sway
VA
S A
lertne
ss P
ape
r (m
m)
20
30
40
50
60
70
80
90
Time (min)
-120 0 120 240 360 480 600
Psyched
elic V
AS
11 (m
m)
-10
0
10
20
30
40
50
60
70
80
Time (min)
-120 0 120 240 360 480 600
0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0
T i m e (m i n )
5 0
6 0
7 0
8 0
9 0
1 0 0
Hea
rt r
ate
(bpm
)
T HC Pl a c e b o
Heart Rate
development of THC challenge and PK/PD-model
isolation of THC for inhalation
Pharmacologically active doses of surinabant: peripheral effects
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
60mg SD 10mg MD
20mg SD 5mg MD
5 mg SD 2.5mg MD
up to 40% peripheral suppression
HR
red
uct
ion
rat
e (%
)
SD dose (mg )
dose-dependent suppression of THC-effects PK/PD-analysis
Time from surinabant dose (h)
-1 0 1 2 3 4 5 6 7 8 9 10
Mea
n (
SD
) H
R (
bpm
)
60
70
80
90
100 Observed SR
Population SR 0 mg
Population SR 5 mg
Population SR 20 mg
Population SR 60 mg
Pharmacologically active doses of surinabant: central effects
dose-dependent suppression of THC-effects
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)
PK/PD-analysis
60mg SD 10mg MD
VA
S h
igh
red
uct
ion
rat
e (%
)
SD dose (mg )
60% central suppression
-9 0 -3 0 3 0 9 0 1 5 0 2 1 0 2 7 0 3 3 0 3 9 0 4 5 0 5 1 0 5 7 0
Tim e (m in )
0
2 0
4 0
6 0
8 0
1 0 0
VA
S F
ee
lin
g h
igh
(m
m)
placebo 2. 5 m g 5 m g 10 m g r im onabant 20 m g
0.00
0.50
1.00
1.50w
eig
ht
cha
ng
e d
uri
ng
sm
oki
ng
ce
ssa
tio
n (
kg)
surinabant (all treated) (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
Phase IIa clinical trail: weight gain during smoking cessation
CB1-inhibition 10% 20% 40% 40%
CB1-inhibition of clinically active rimonabant dose: central (60%) > peripheral (40%) suppression rates
60mg SD 20mg MD
60mg SD 20mg MD
weight reduction? < psychiatric adverse effects?
5mg SD 5mg MD
Peripherally restrictive CB1-antagonists: improved therapeutic window?
drinabant 40% peripheral → 30% central suppression
TM38837 40% peripheral → 15% central suppression
weight reduction? >> 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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