Eisai Inc's Aricept

In October 2006, the FDA approveddonepezil HCl (Aricept) for patients diagnosedwith severe Alzheimer's disease(AD).¹ Donepezil, a cholinesterase inhibitor,was approved for mild-to-moderateAD in 1996.² It is only the seconddrug, after memantine, approved forsevere dementia.

The approval was based on the resultsof 2 clinical trials submitted by the sponsor,Eisai Inc. Together, the 2 studiesshowed that patients with severedementia who received donepezil performedbetter on cognitive functions,such as memory, language, orientation,and attention.¹ Decreases in acetylcholineare thought to be associatedwith the loss of cognitive functions,including memory. Therefore, inhibitingthe breakdown of this neurotransmitteris an important pharmacologic therapyfor AD.³

Clinical Trials

A 6-month, double-blind, placebo-controlledstudy enrolled 248 patients diagnosedwith severe dementia from variousSwedish nursing homes.^4,5 Thepatients were randomized to receiveeither active donepezil or placebo. In theactive arm, the patients receiveddonepezil 5 mg once daily for 30 days;then the dose was titrated to 10 mgdaily. Ninety-five patients assigned todonepezil and 99 patients assigned toplacebo completed the study.⁵

The primary outcomes were measuredusing the Severe Impairment Battery(SIB) and the Alzheimer's DiseaseCooperative Study Activities of DailyLiving Inventory for Severe AD (ADCSADL-severe).⁴ The SIB scale is a validatedinstrument that measures the severity ofcognitive dysfunction in advanced AD interms of memory, language, orientation,attention, praxis, visuospatial construction,ability to name people and objects,and social interaction. The ADCS-ADLsevereis a 19-item scale used to measurebasic activities of daily living, such aseating and bathing, and complex abilities,such as opening water taps and switchingon lights, with scores ranging fromzero to 54.⁴ Severe dementia was definedusing the Mini-Mental StateExamination scores of 1 to 10.^4,5 At 6months, the donepezil-treated group hadhigher SIB scores by a mean of 5.7 points(P = .008) and higher ADCS-ADL-severescores by a mean of 1.7 points (P = .03),compared with placebo.^4,5

The second 6-month study, which wasconducted in Japan, included 325patients diagnosed with AD. Patientswere randomized to receive 5 mg/day,10 mg/day, or matching placebo for 6months. Improvement was measuredusing the SIB and the Clinician's Interview-Based Impression of Change PlusCaregiver Input (CIBIC-Plus).^4,5 On the SIBscale, the donepezil 10-mg groupimproved by a mean of 4.7 points; thedonepezil 5-mg group improved by amean of 2.5 points; and the patients whoreceived placebo demonstrated a declineof 4.2 points. At both doses, the differencebetween the treatment groupsand placebo was statistically significant.Only the donepezil 10-mg group was statisticallyfavorable on the CIBIC-Plusscale.^4,5

Donepezil was titrated in both studiesto minimize cholinergic side effects. Themost common side effects included diarrhea,nausea, vomiting, insomnia, musclecramp, fatigue, and anorexia.⁴ The sideeffects generally subsided with continueddonepezil therapy. The patient'sresponse should be monitored with the5-mg/day dose for 4 to 6 weeks beforetitrating up to 10 mg, because the rate ofthe common adverse events may beaffected by the rate of titration.⁴

Pharmacokinetics

Donepezil reaches peak plasma concentrationsin 3 to 4 hours and has anelimination half-life of 70 hours.⁴ It ismetabolized by the isoenzymes CYP2D6and CYP3A4 and undergoes glucuronidation.⁴ No dosage adjustment isnecessary in patients with renal disease,and the clearance of donepezilwas decreased by 20% in patients withstable alcohol cirrhosis.⁴

Conclusion

More clinical trials are needed tostudy the AD patients who are notnaive to cholinesterase inhibition therapy.Aricept is available in 5-and 10-gtablets. Aricept Orally DisintegratingTablets (ODT) also are available in 5-and 10-mg strengths, for patients whohave difficulty swallowing tablets.Aricept ODT is bioequivalent to Aricepttablets and may be taken with or withoutfood.

Ms. Domenici and Dr. Patel are bothpharmacists at Brigham andWomen's Hospital, Boston, Mass. Mr.Exter is a sixth-year PharmD candidatefrom Northeastern UniversitySchool of Pharmacy currently on clinicalclerkship in the InvestigationalDrug Service at Brigham andWomen's Hospital.

References

1. www.eisai.com/view_press_release.asp?ID=147&press=150. Accessed February20, 2007.

2. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed February 20, 2007.

3. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. TheCochrane Library, Copyright 2006, The Cochrane Collaboration Volume (4),2006.

4. Teaneck, NJ: Eisai Inc. Aricept Package Insert. Revised October 2006.

5. Teaneck, NJ: Eisai Inc. Health Professional Letter.