Pharmacotherapy, clinical pharmacology and biomarker ... geriatric patients2,3. Evaluation of medication

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  • Pharmacotherapy, clinical pharmacology and biomarker research in geriatric patients

  • ISBN-10: 90-393-4419-1 ISBN-13: 978-90-393-4419-4 © 2006 Suzanne V. Frankfort, Utrecht Printed by: Ponsen & Looijen BV, Wageningen, The Netherlands Cover design: “Proefschrift Memory”, Martijn van Dalen, Utrecht

  • Pharmacotherapy, clinical pharmacology and biomarker research in geriatric patients

    Farmacotherapie, klinische farmacologie en onderzoek naar biologische markers in geriatrische patiënten

    (met een samenvatting in het Nederlands)


    ter verkrijging van de graad van doctor aan de Universiteit Utrecht

    op gezag van rector magnificus, prof. dr. W.H. Gispen, ingevolge het besluit van het college voor promoties

    in het openbaar te verdedigen op woensdag 10 januari 2007 des middags te 2.30 uur


    Suzanne Viola Frankfort

    geboren op 31 juli 1978 te Gendringen

  • Promotor: Prof. Dr J.H. Beijnen Publication of this thesis was financially supported by: Janssen-Cilag BV, Tilburg, The Netherlands Stichting KNMP fondsen, Den Haag, the Netherlands Department of Pharmaceutical Sciences, Utrecht, The Netherlands Netherlands Laboratory for Anticancer Drug Formulation (NLADF), Amsterdam, The Netherlands Internationale Stichting Alzheimer Onderzoek, Maastricht, The Netherlands Wyeth Pharmaceuticals BV, Hoofddorp, The Netherlands Lundbeck BV, Amsterdam, The Netherlands AstraZeneca BV, Zoetermeer, The Netherlands

  • The studies described in this thesis were performed at the department of Geriatric Medicine and the department of Pharmacy & Pharmacology of the Slotervaart Hospital, Amsterdam, The Netherlands.

  • Contents Preface 9 Chapter 1 Pharmacotherapy of geriatric patients 13

    1.1 Evaluation of pharmacotherapy in geriatric patients after performing 15 Complete Geriatric Assessment (CGA) at a diagnostic day-clinic

    1.2 The effect of admission to a geriatric ward on medication use: 2002 25 versus 1985

    Chapter 2 Digoxin 33

    2.1 Role of ABCB1 genotypes and haplotypes in digoxin steady state 35 pharmacokinetics in geriatric patients

    Chapter 3 Rivastigmine 49 Chapter 3.1 Bioanalysis of rivastigmine 51

    3.1.1 A simple and sensitive assay for the quantitative analysis of 53 rivastigmine and its metabolite NAP 226-90 in human EDTA plasma using coupled liquid chromatography and tandem mass spectrometry

    Chapter 3.2 Rivastigmine pharmacotherapy and clinical pharmacology 71

    3.2.1 Discontinuation of rivastigmine in routine clinical practice 73 3.2.2 Treatment effects of rivastigmine on cognition, performance of daily 81 living activities and behaviour in Alzheimer’s disease in an out- patient geriatric setting 3.2.3 Identification of responders and reactive domains to rivastigmine in 99 Alzheimer’s disease

  • 3.2.4 Population pharmacokinetics and pharmacodynamics of 111 rivastigmine and its metabolite NAP 226-90 in patients with dementia

    Chapter 4 Biomarkers for dementia 129 Chapter 4.1 Genetic biomarkers 131

    4.1.1 APOE genotype and allele distribution in geriatric outpatients and 133 healthy volunteers 4.1.2 ABCB1 genotypes and haplotypes in patients with dementia and 141 age-matched non-demented control patients

    Chapter 4.2 Proteomic biomarkers 149

    4.2.1 Amyloid beta protein and tau in cerebrospinal fluid and plasma as 151 biomarkers for dementia: a review of recent literature 4.2.2 Cerebrospinal fluid biomarkers found for Alzheimer’s disease and 169 Vascular Dementia using Surface-Enhanced Laser Desorption Ionisation-Time of Flight Mass Spectrometry (SELDI-TOF MS) 4.2.3 Serum amyloid beta peptides in patients with dementia and age- 185 matched non-demented controls as detected by Surface-Enhanced

    Laser Desorption Ionisation- Time of Flight Mass Spectrometry (SELDI-TOF MS)

    Conclusions and Perspectives 201 Summary 205 Samenvatting 211 Dankwoord 217 Curriculum Vitae 221 List of Publications 222

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    Preface Optimisation of pharmacotherapy and research into the diagnosis of different types of dementia (Alzheimer’s disease, vascular dementia, Lewy body disease, frontotemporal disease) and treatment of dementia are of primary importance within the field of geriatric medicine. Challenges in the dementia field are optimisation of the current symptomatic therapy with cholinesterase inhibitors, the development of disease-modifying therapies and diagnosing dementia as early as possible before the biological processes have already started. Biomarker research in body fluids, for example cerebrospinal fluid and serum/plasma, plays an important role in early diagnostics. First, this thesis deals with optimisation of general pharmacotherapy and clinical pharmacological investigations of digoxin, a frequently used drug, in geriatric patients. Second, this thesis aims to gain further insight into rivastigmine therapy, an example of a symptomatic cholinesterase inhibitor, in outpatients with Alzheimer’s disease. Third, the thesis deals with the development of biological markers for the diagnosis of dementia. The number of elderly patients that visit the department of Geriatric Medicine is growing due to the increase of the number of elderly in the population. Geriatric patients often suffer from complex co-morbidity and subsequent use of multiple drugs. This may lead to an increase in drug-drug interactions and incidence of adverse events1. It is thus important to reduce polypharmacy, but it is recognised, however, that undertreatment is also apparent in geriatric patients2,3. Evaluation of medication in the elderly should aim to reduce polypharmacy on the one hand and prevent undertreatment on the other. This thesis deals with pharmacotherapy in geriatric patients when they visit the diagnostic day-clinic (chapter 1.1) and the geriatric ward (chapter 1.2) and with the changes that are made after pharmacotherapy evaluation by a geriatrician. Clinical pharmacological research in the geriatric population is still in its infancy as patients aged over 65 are frequently excluded from this type of clinical research. This thesis deals with the role that ABCB1 genotypes may play in the steady-state pharmacokinetics of digoxin in geriatric patients using digoxin as part of their therapeutic regimen (chapter 2.1). Rivastigmine is one of the registered cholinesterase inhibitors for the treatment of mild-to- moderate Alzheimer’s disease4,5. It is known, however, that patients using rivastigmine often discontinue therapy and that treatment effects of rivastigmine differ substantially between individuals6. The rate of and reason for discontinuation in clinical practice and possible risk factors for discontinuation within the first 6 months of treatment were investigated (chapter 3.2.1). In addition, research investigating treatment effects of rivastigmine during 30 months (chapter 3.2.2) and reactive domains and characteristics of responders (chapter 3.2.3) are described. A population pharmacokinetic model was developed for rivastigmine and its metabolite NAP226-90 and pharmacokinetic parameters

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    were estimated and related to outcome measures (cognition, activities in daily living, behaviour) to investigate whether differences in pharmacokinetics may explain differences in treatment effects (chapter 3.2.4). With the advance of new disease-modifying therapies, for example the secretase- inhibitors7, it becomes important to establish an early dementia diagnosis. Biological markers of genetic origin may add to the dementia diagnosis (chapter 4.1.1 and 4.1.2). Chapter 4.2.1 summarises recent developments in the use of amyloid β and tau protein in cerebrospinal fluid and plasma as biomarkers for dementia. Proteomics can be used to identify possible biomarkers in biological fluids. Using the new method Surface Enhanced Laser Desorption/Ionisation-Time of Flight Mass Spectrometry (SELDI-TOF MS), biomarkers for Alzheimer’s disease and vascular dementia were investigated in cerebrospinal fluid (chapter 4.2.2) and in serum (chapter 4.2.3).

    References 1. Stewart RB, Cooper JW. Polypharmacy in the aged: practical solutions. Drugs Aging 1994;4: 449-61. 2. Mendelson G, Aronow WS. Underutilization of warfarin in older persons with chronic nonvalvular atrial

    fibrillation at high risk for developing stroke. J Am Geriatr Soc 1998; 46: 1423-1424. 3. Ghosh S, Ziesmer V, Aronow WS. Underutilization of aspirin, beta blockers, angiotensin-converting enzyme

    inhibitors, and lipid-lowering drugs and overutilization of calcium channel blockers in older persons with coronary artery disease in an academic nursing home. J Gerontol A Biol Sci Med Sci 2002; 57: 398-400.

    4. Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. International Journal of Geriatric Psychopharmacology 1998; 1:55-65.

    5. Rösler M, Anand R, Cican-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzhe