Abstract
Alzheimer’s disease (AD) is the most commonly occurring dementia and consists of both cognitive impairment and behavioral disturbances. Two types of medication classes are approved by the regulatory agencies for AD treatment. The cholinesterase inhibitors (ChEIs) are used for patients with mild, moderate, and severe AD. Memantine (MEM) is indicated for moderate to severe AD patients. ChEIs and MEM are often combined together for treatment. The pharmacokinetics (PK) of the ChEIs is well known. Donepezil and galantamine display linear PK, whereas rivastigmine has nonlinear PK. Donepezil and galantamine are metabolized by the CYP2D6 and CYP3A4 enzymes. Rivastigmine is metabolized by the hepatic esterases. MEM is not significantly metabolized by the hepatic enzymes and is primarily excreted by the kidneys. Dosage adjustments are recommended for patients with severe hepatic and renal impairment. The clinical pharmacodynamic (PD) properties for the ChEIs and MEM can be assessed by various biomarkers that include cholinesterase enzyme inhibition, clinical rating scales for cognitive impairment and behavioral symptoms, and PET scan evaluations. Pharmacogenetic status is in its early utilization phase of clinical utility in AD patients. PET scans may provide useful information on patient response to ChEIs and MEM. The gastrointestinal adverse side effects limit ChEIs, but these effects are transient and associated with dose titration. Population PK analysis can integrate the PK, PD, and pharmacogenetic data to optimize treatment in patients with AD.
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References
Slattum PW, Peron EP, Hill AM (2014) Alzheimer’s disease. In: DiPiro JT, Talbert RL, Yee GC et al (eds) Pharmacotherapy: a pathophysiologic approach, 9th edn. McGraw-Hill, New York, pp 817–833
Steele CD, Steinberg M, Milles G, Jann MW (1999) Recognition and management of early Alzheimer’s disease. JCOM 6:52–67
Seltzer B (2007) Donepezil: an update. Expert Opin Pharmacother 8:1011–1023
Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA (2000) Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol 48:391–395
Jann MW, Small GW (2009) Cholinesterase inhibitors and similarly acting compounds. Chapter 31.15. In: Sadock BJ, Sadock VA, Ruiz R (eds) Comprehensive textbook of psychiatry, 9th edn. Lippincott, Williams, and Wilkens, Philadelphia, PA, pp. 3089–3099
Noetzli M, Eap CB (2013) Pharmacodynamic, pharmacokinetic, and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 52:225–251
Jann MW (1998) Pharmacology and clinical efficacy of cholinesterase inhibitors. Am J Health Syst Pharm 55(Suppl 2):S22–S25
Jann MW, Grossberg G (2000) Cholinesterase inhibitors in the treatment of Alzheimer’s disease. Consult Pharm 15(Suppl B):7–15
Mihara M, Ohnishi A, Tomono Y et al (1993) Pharmacokinetics of E2020, a new compound for Alzheimer’s disease, in healthy male volunteers. Int J Clin Pharmacol Ther Toxicol 31(5):223–229
Rogers SL, Friedhoff LT (1998) Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br J Clin Pharmacol 46(Suppl 1):1–6
Eisai (2014) ARICEPT® (donepezil hydrochloride) tablets: prescribing information. Eisai Inc., Woodcliff Lake, NJ
FDA (2010) Application number: 022568. Center for Drug Evaluation and Research; Clinical Pharmacology and Biopharmaceutics Review(s)
Rogers C, Sukovaty P, Lee F (1998) Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses. Br J Clin Pharmacol 46(S1):7–12
Tiseo PJ, Perdomo CA, Friedhoff LT (1998) Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol 46(Suppl 1):19–24
Ohnishi A, Mihara M, Kamakura H et al (1993) Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer’s disease, in healthy young and elderly subjects. J Clin Pharmacol 33:1086–1091
Haywood WM, Mukaetova-Ladinska EB (2006) Sex influences on cholinesterase inhibitor treatment in elderly individuals with Alzheimer’s disease. Am J Geriatr Pharmacother 4:273–286
Griffith P, Lichtenberg P, Goldman R, Payne-Parrish J (2006) Safety and efficacy of donepezil in African Americans with mild-to-moderate Alzheimer’s disease. J Natl Med Assoc 98:1590–1597
Nagy CF, Kumar D, Cullen EI et al (2004) Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function. Br J Clini Pharmacol 58(Suppl 1):18–24
Reyes JF, Vargas R, Kumar D, Cullen EI, Perdomo CA, Pratt RD (2004) Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients. Br J Clin Pharmacol 58(Suppl 1):9–17
Nordberg A, Svensson A-L (1998) Cholinesterase inhibitors in the treatment of Alzheimer’s disease. Drug Saf 19:465–480
Jann MW, Shirley KL, Small GW (2002) Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 41:719–739
Polinsky RJ (1998) Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther 20:634–647
Anand R, Gharabawi G, Enz A (1996) Efficacy and safety results of the early phase studies with Exelon (TM)(ENA-713) in Alzheimer’s disease: an overview. J Drug Dev Clin Pract 8:109–116
Novartis (2015) Exelon® Patch (rivastigmine transdermal system), full prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ
Kennedy JS, Polinsky RJ, Johnson B et al (1999) Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. J Clin Psychopharmacol 19:513–521
Spencer CM, Noble S (1998) Rivastigmine. A review of its use in Alzheimer’s disease. Drugs Aging 13:391–411
Williams BR, Nazarians A, Gill MA (2003) A review of rivastigmine: a reversible cholinesterase inhibitor. Clin Ther 25:1634–1653
Cutler NR, Polinsky RJ, Sramek JJ et al (1998) Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer’s disease. Acta Neurol Scand 97:244–250
Krall WJ, Sramek JJ, Cutler NR (1999) Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease. Ann Pharmacother 33:441–450
Janssen (2013) RAZADYNE® ER (galantamine hydrobromide) full prescribing information. Janssen Pharmaceuticals, Inc., Titusville, NJ
Farlow MR (2003) Clinical pharmacokinetics of galantamine. Clin Pharmacokinet 42:1383–1392
VanDenBerg CM, Kazmi Y, Jann MW (2000) Cholinesterase inhibitors for the treatment of Alzheimer’s disease in the elderly. Drugs Aging 16:123–138
Zhao Q, Iyer GR, Verhaeghe T et al (2002) Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers. J Clin Pharmacol 42:428–436
Gomolin JH, Smith C, Jeitner TM (2011) Cholinesterase inhibitors: applying pharmacokinetics to clinical decision making. Am J Geriatr Pharmacother 9:259–263
Noetzli M, Guidi M, Ebbing K et al (2014) Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR, NR1/2 genotypes on donepezil clearance. Br J Clin Pharamacol 78:135–144
Piotrovsky V, Van Peer A, Van Osselaer N et al (2003) Galantamine population pharmacokinetics in patients with Alzheimer’s disease: modeling and simulation. J Clin Pharmacol 43:514–523
Gobburu JV, Tammara V, Lesko L et al (2001) Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer’s disease. J Clin Pharmacol 41:1082–1090
Hossain M, Jhee SS, Shiovitz T et al (2002) Estimation of the absolute bioavailability of rivastigmine in patients with mild-moderate dementia of the Alzheimer’s type. Clin Pharmacokinet 41:225–234
Holford NH, Sheiner LB (1982) Kinetics of pharmacologic response. Pharmacol Ther 16:143–166
Sramek JJ, Cutler NR (2000) RBC cholinesterase inhibition: a useful surrogate marker for cholinesterase inhibitor activity in Alzheimer’s disease therapy? Alzheimer’s Dis Assoc Disord 14:216–227
Weinstock M (1999) Selectivity of cholinesterase inhibition: clinical implications for the treatment of Alzheimer’s disease. CNS Drugs 12:307–323
Chianella C, Gragnaniello D, Maisanio Delser P et al (2011) BCHE and CYP2D6 genetic variation in Alzheimer’s disease patients treated with cholinesterase inhibitors. Eur J Clin Pharmacol 67:1147–1157
Yang YH, Chen CH, Chou MC et al (2013) Concentration of donepezil to the cognitive response in Alzheimer’s disease. J Clin Psychopharmacol 33:351–355
Jann MW (2000) Rivastigmine, a new generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy 20:1–12
Farlow MR, Salloway S, Tariot PN et al (2010) Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) in moderate to severe Alzheimer’s disease: a 24-week, randomized, double-blind study. Clin Ther 32:1234–1251
Christensen DD (2012) Higher dose (23 mg/day) donepezil formulation for the treatment of patients with moderate-severe Alzheimer’s disease. Postgrad Med 124:110–116
Okamura N, Funaki Y, Tashiro M et al (2008) In vivo visualization of donepezil binding in the brain of patients with Alzheimer’s disease. Br J Clin Pharmacol 65:472–479
Shimada A, Hashimoto H, Kawabe J et al (2011) Evaluation of therapeutic response to donepezil by positron emission tomography. Osaka City Med J 57:11–19
Kasuya M, Meguro K, Okamura N et al (2012) Greater responsiveness to donepezil in Alzheimer’s patients with higher levels of acetylcholinesterase based on attention task scores and a donepezil PET study. Alzheimer’s Dis Assoc Disord 26:113–118
Potkin S, Anand R, Fleming K et al (2001) Brain metabolic and clinical effects of rivastigmine in Alzheimer’s disease. Int J Neuropsychopharmacol 4:223–230
Stefanova E, Wall A, Almkvist O et al (2006) Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer’s disease. J Neural Transm 113:205–218
Kadir A, Darreh-Shori T, Almkvist O et al (2007) Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET. Psychopharmacology 191:1005–1014
Mega MS, Dinov ID, Porter V et al (2005) Metabolic patterns associated with the clinical response to galantamine therapy. Arch Neurol 62:721–728
Darreh-Shori T, Kadir A, Almkvist O et al (2008) Inhibition of acetylcholinesterase in CS versus brain assessed by 11C-PMP PET in AD patients treated with galantamine. Neurobiol Aging 29:168–184
Kadir A, Darreh-Shori T, Almkvist O et al (2008) PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging 29:1204–1217
McKeage K (2009) Memantine: a review of its use in moderate to severe Alzheimer’s disease. CNS Drugs 23:881–897
Atri A, Hendrix SB, Pejovic V et al (2015) Cumulative, additive benefits of memantine-donepezil combination component monotherapies in moderate-to-severe Alzheimer’s dementia: a pooled area under the curve analysis. Alzheimers Res Ther 7(1):28. doi:10.1186/s13195-015-0109-2
Kornhuber J, Kennepohl EM, Bleich S et al (2001) Memantine pharmacotherapy. Clin Pharmacokinet 46:599–612
Periclou A, Ventura D, Rao N, Abramowitz W (2006) Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 79:134–143
Moritoyo T, Hasunuma T, Harada K et al (2012) Effect of renal impairment on the pharmacokinetics of memantine. J Pharmacol Sci 119:324–329
Noetzli M, Guidi M, Ebbing K et al (2013) Population pharmacokinetic study of memantine: effects of clinical and genetic factors. Clin Pharmacokinet 52:211–223
Gomolin IH, Smith C, Jietner TM (2010) Once-daily memantine pharmacokinetic and clinical considerations. JAGS 58:1812–1813
Lam S, Smith C, Gomolin IH (2015) Memantine standard tablet and extended-release dosing considerations: a pharmacokinetic analysis. JAGS 63:183–184
Kornhuber J, Quack G (1995) Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett 195:137–139
Jones RW, Bayer A, Inglis F, Barkers A, Phul R (2007) Safety and tolerability on once-daily versus twice-daily memantine: a randomized, double-blind study in moderate to severe Alzheimer’s disease. Int J Geriatr Psychiatry 22:258–262
Grossberg GT, Manes F, Allegri RF et al (2013) The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs 27:469–478
Ametamey SM, Bruehlmeier M, Kneifel S et al (2002) PET studies of 18F-memantine in healthy volunteers. Nucl Med Biol 29:227–231
Chow TW, Graff-Guerrero A, Verhoeff NP et al (2011) Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia. Neuropsychiatr Dis Treat 7:415–424
Chow TW, Farm D, Graff-Guerrero A et al (2013) FDG-PET in semantic dementia after 6 months of memantine: an open-label study. Int J Geriatr Psychiatry 28:319–325
Sultzer DL, Melrose RJ, Harwood DG, Campa O, Mandelkern MA (2010) Effects of memantine treatment on regional cortical metabolism in Alzheimer’s disease. Am J Geriatr Psychiatry 18:606–614
Wang T, Huang Q, Reiman EM et al (2013) Effects of memantine on clinical ratings, fluorodeoxyglucose positron emission tomography measurements, and cerebrospinal fluid assays in patients with moderate to severe Alzheimer’s dementia. J Clin Psychopharmacol 33:636–642
Prvulovic D, Schneider B (2014) Pharmacokinetic and pharmacodynamics evaluation of donepezil for the treatment of Alzheimer’s disease. Expert Opin Drug Metab Toxicol 10:1039–1050
Small GW, Bullock R (2011) Defining optimal treatment with cholinesterase inhibitors in Alzheimer’s disease. Alzheimer’s Demen 7:177–184
Zhong Y, Zheng X, Miao Y et al (2013) Effect of CYP2D6*10 and APOE polymorphisms on the efficacy of donepezil in patients with Alzheimer’s disease. Am J Med Sci 34:222–226
Noetzli M, Guidi M, Ebbing K et al (2013) Relationship of CYP2D6, CYP3A, POR, ABCB1, genotypes with galantamine steady-state plasma concentrations. Ther Drug Monit 35:270–275
Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR (2002) Inhibition of acetyl – and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer’s disease by rivastigmine: correlation with cognitive benefit. J Neural Transm 109:1053–1065
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VanDenBerg, C.M., Jann, M.W. (2016). Antidementia Drugs. In: Jann, M., Penzak, S., Cohen, L. (eds) Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Adis, Cham. https://doi.org/10.1007/978-3-319-27883-4_13
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