Studiesin thegeriatric population

Transcription

1 Studiesin thegeriatric population Petra A. Thürman HELIOS Klinikum Wuppertal

2 Drug use across all age groups in Germany men women > 65-years old persons receive 4-5 different drugs/day > 50 % of all octagenarians receive 5 different drugs/day Thürmann et al, Versorgungs-Report

3 Representation of elderly patients in oncology trials submitted to the FDA Mean age of diagnosis in Germany: 72 years 55 trials with drugs approved between 1995 and 2002 Talarico et al, J Clin Oncol

4 Heart failure trials and age of patients enrolled Median age of trial participants versus median age in the Würzburg Heart Failure Registry 3

5 Demographic Development and issues for consideration for drug development Altered pharmacokinetics and -dynamics Multimorbidity Polypharmacy Interactions Adverse drug reactions Statistisches Bundesamt Benefit/Risk-Ratio? Cho et al, Arch Intern Med

6 Definition of age groups newborns (birth to 3 months) infants (3 months to 2 yrs) children (2 to 12 yrs) adolescents (12 to 18 years) ADULTS elderly (> 65 yrs) 5

7 Definition of age groups newborns (birth to 3 months) infants (3 months to 2 yrs) children (2 to 12 yrs) adolescents (12 to 18 years) ADULTS elderly (> 65 yrs) old (75 yrs < 85 yrs) very old (85 yrs to 100) centenarians (100 yrs and above) 6

8 Definitions of age and functional decline Calendar age socio-psycho-biological age Biological age Frailty - reduced reserve, impaired homeostatic function, reduced stressresistance based on - decline of physiological functions such as Muscle mass (sarcopenia), neuroendocrine function, immune system - resulting in an increased vulnerability to adverse events (Rockwood, Age Aging 2005) Functional parameters and tests: - Charlson Index, Cumulative Illness Rating Scale, Functional Comorbidity Index (Fortin et al, 2005) - Handgrip Test, Timed up and go-test, Tinetti Test, MMSE, 7

9 Some biomarkers of aging Rosenberg, J Nutr 1997 Koster et al, JAGS

10 Development of body composition..? 9

11 Kreatinin-Clearance and age: a rough estimate Cl = (140 age) x body weight (kg) men 72 x serum creatinine Cl = (140 age) x body weight (kg) women 85 x serum Creatinine 10

12 Database for physiologically-based pharmacokinetic modeling VENOUS BLOOD POOL VENOUS BLOOD POOL i.v. i.v. DOSE DOSE p.o. p.o. PORTAL VEIN PORTAL VEIN STOMACH STOMACH WALL WALL SMALL INTESTINE SMALL INTESTINE WALL WALL LARGE INTESTINE LARGE INTESTINE WALL WALL PANCREAS PANCREAS SPLEEN SPLEEN LIVER LIVER KIDNEY KIDNEY TESTES TESTES HEART HEART BRAIN BRAIN FAT BONE FAT BONE SKIN MUSCLE SKIN MUSCLE LUNG LUNG GALL BLADDER GALL BLADDER ARTERIAL BLOOD POOL ARTERIAL BLOOD POOL Age-associated changes relevant for PK: Body weight and composition Renal function, metabolism (CYP and transporter function) Tissue blood flow, tissue weight Heart and lung function Frequent comorbidities Willmann et al., Biosilico 1(4), (2003) Thompson et al, J Toxicol Environment Health

13 Database for physiologically-based pharmacokinetic modeling Thompson et al, J Toxicol Environment Health

14 Population analysis of atorvastatin clearance in patients living in the community and in nursing homes Schwartz & Verotta, CPT

15 Population analysis of atorvastatin clearance in patients living in the community and in nursing homes Schwartz & Verotta, CPT

16 Decline of cognitive functions associated with anticholinergic drugs over 4 years (3 Cities Study) Test Women odds ratio Men odds ratio ΔIST Isaac -6 Set Test discontinuing verbal fluency continuing ΔBVRT Benton -2 Visual discontinuing Retention Test continuing verbal memory ΔTMT Trail A Making 16 Test A discontinuing Psychomotor speed continuing ΔTMT Trail B Making 16 Test B discontinuing Psychomotor executive continuing function ΔMMSE Minimental -2 State discontinuing Examination continuing Global cognitive function 1.49 ( ) 1.53 ( )* 0.90 ( ) 1.27 ( ) 0.81 ( ) 1.14 ( ) 1.06 ( ) 0.92 ( ) 1.07 ( ) 1.48 ( )* 0.63 ( ) 1.48 ( ) 1.18 ( ) 2.07 ( )* 0.49 ( ) 1.12 ( ) 0.97 ( ) 2.23 ( )* 1.34 ( ) 1.41 ( ) Carriere et al, Arch Intern Med

17 CNS penetration potential of overactive bladder agents Callegari et al, BJCP

18 CNS penetration potential of overactive bladder agents Drug Predicted CNS penetration P-gp substrate CNS penetration in rats in vivo Trospium Not significant Yes Not significant Clinical effects NR Fesoterodine Darifenacin Solifenacin Tolterodine Oxybutynin Significant Significant Significant Significant significant Yes Yes No No No Not significant Not significant Significant Significant Significant NR ~ 2 % dizziness ~ 2 % dizzines Somnolence somnolence Callegari et al, BJCP

19 TRITON-TIMI-38 Subgroup analyses Previous Stroke/TIA Ja Nein P int = Risk (%) Age >=75 < 75 P int = weight < 60 kg +3 >=60 kg P int = OVERALL -13 Prasugrel 1 HR Clopidogrel 18

20 Thrombolysis with alteplase in acute stroke 19

21 Thrombolysis with alteplase in acute stroke 20

22 Thrombolysis with alteplase in acute stroke In clinical trials submitted to the EMA/FDA patients > 80 years were excluded! Very old patients have a poorer prognosis than younger old patinets 21

23 Benefit of thrombolysis in octagenarians SITS-ISTR (Registry) versus Placebo-treated controls from thrombolysis studies (VISTA) Mishra et al, BMJ

24 Current Guidance/Guidelines for the Geriatric population Patients entering clinical trials should be reasonably representative Geriatric: age 65 and older 75 y. and above to the extent possible in Phase 2/3 approx. 100 geriatrics PK related to renal function formal PK studies in elderlies not mandatory, sparse sampling from phase 2/3 trials PD: focussing on CNS (side) effects 23

25 Adequacy of guidance on the elderly regarding medicinal products for human use Age cut offs and definition of frailty should be defined by the European Union of Geriatric Medicine Society (EUGMS) Reviews how current guidelines (CHMP, EWP etc.) address ICH E 7 - Some of them need improvement, e.g. urinary incontinence in women Analyses of 10 recently approved drugs (CHMP assessment reports) CHMP, doc.ref. EMEA/498920/

26 How was ICH E 7 addressed in the assessment report of duloxetine? Okay, > 100 One additional study in the elderly was requested: phase III with 206 elderlies, only 64 were > 75 years. 25

27 Current Guidance/Guidelines for the Geriatric population N = 100 no longer sufficient > 65 years, but also very elderly Other endpoints (QoL, function) rather than living longer Access to trials (!) Frailty Adapted dosages and formulations PopKin or formal PK-studies In some indications, e.g. Parkinson, strata > 75 and > 85 Adequate characterisation of safety in very elderly!! Development plan Specific elements in trials to consider comorbidities/comedication 26

28 Current Guidance/Guidelines for the Geriatric population Every effort should be made to include geriatric patients in clinical trials enrollment of these patients could be challenging CDER, FDA February 2012 insufficient, a specific plan to collect data postmarketing should be presented Age-related efficacy endpoints and adverse effects, e.g. cognition, falls, urinary retention should be actively thought in the geriatric population 27

29 Identification of current gaps in guidelines and knowldege Updating current regulatory guidelines Specific pharmacovigilance acitivities (e.g. ENCePP project ADR related hospitalisations in the geriaric population in Europe chaired by Ulf Bergman) Provide advice to applicants in this regard Fostering and using an expert pool Template of the assessment report will include a new section for geriatric population CHMP Advisory group on geriatrics now established 28

30 EMA: Medicines for older people The Geriatric Expert Group (GEG) provides scientific advice to the Committee for Medicinal Products for Human Use (CHMP) and the European Medicines Agency secretariat on issues related to the elderly. Its work includes: giving input related to geriatrics on guidelines under consultation; giving advice on geriatric aspects of the development, assessment or safety monitoring of medicines; taking part in meetings where expertise on geriatrics is needed; contributing to the geriatric implementation plan. _ jsp&mid=WC0b01ac058004cbb9&jsenabled=true 29

31 Barriers to include elderly patients in clinical drug trials In/exclusion criteria Old Age Comorbidities, comedication Life expectancy Difficulties of communication Explanation of informed consent / involving family and caregivers study-associated office/hospital visits (mobility) Ethical aspects in dementia 30

32 European Medicines Agency workshop on medicines for older people Date: 22/03/ /03/2012 Location: European Medicines Agency, London, UK The European Medicines Agency is hosting a two-day workshop on medicines for older people. Although speakers will be by invitation and capacity will be limited, the Agency is inviting interested experts and stakeholders to send an expression of interest to attend this workshop by 9 December 2011 to geriatricsworkshop@ema.europa.eu. 31

33 Thank you! 32