Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 Nat Rev Drug Discov. 2010;9:856-65 …25 Drugs Withdrawn After Launch… Drug amineptine (Survector) cisapride (Propulsid) troglitazone (Rezulin) alosetron (Lotronex) phenylpropanolamine (Dexatrim) cerivastatin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1997 1999 1998 1993 1999 1975 2004 2004 2004 2004 1988 2004 2006 1993 2006 2003 1988 2000 2001 Withdrawn License 2000 2000 2000 2000 2000 2001 2001 2001 2003 2004 2005 2005 2005 2005 2005 2007 2007 2008 2008 2008 2009 2010 2010 2011 pharmacological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