Pharmacology-Guided Dose-Escalation of First-in-Class Drugs...Pharmacology-Guided Dose-Escalation of First-in-Class Drugs almorexant (ORX1/2-antagonist) and rimonabant (CB1-antagonist)

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…25 Drugs Withdrawn After Launch… Drug Approved Withdrawn License Reason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


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


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

Pharmacology-Guided Dose-Escalation of First-in-Class Drugs...Pharmacology-Guided Dose-Escalation of First-in-Class Drugs almorexant (ORX1/2-antagonist) and rimonabant (CB1-antagonist)

Documents