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Associate Professor Department of Pediatrics Nagasaki University Hospital Sakamoto 1-7-1 Nagasaki 852-8501, Japan fax 81-95-849-7301 kontatsu{at}net.nagasaki-u.ac.jp
Associate Professor Department of Hospital Pharmacy Nagasaki University Hospital
Professor and Head Department of Hospital Pharmacy Nagasaki University Hospital
Professor and Head Department of Pediatrics Nagasaki University School of Medicine
Published Online, February 8, 2005. www.theannals.com, DOI 10.1345/aph.1E512
Methods. A trial of donepezil therapy for patients with Down syndrome was approved by the Ethical Review Committee of Nagasaki University, and informed consent was obtained from the patients' parents. Blood was drawn from 14 patients (9 males) aged 15 to 37 years (mean 26) 24 hours after administration of the last dose on the 28th treatment day. They were free from any other clinical problems at the entry of this trial. Their weight ranged from 42 to 75 kg (mean 58), and IQ ranged from <20 to around 50. Blood was similarly drawn from 6 healthy males (aged 21-27 y). Plasma donepezil concentrations were measured by HPLC.5 When the dose of donepezil was changed, we reevaluated plasma concentrations 28 days after the change.
Results. Plasma donepezil concentrations were distributed widely among patients taking the same dose, and the mean plasma concentrations were 17.9 ± 7.1 and 28.2 ± 3.4 ng/mL for 3 and 5 mg daily, respectively. Plasma concentrations in healthy volunteers taking 2 and 5 mg were 7.8 ± 2.5 and 17.5 ± 2.5 ng/mL, respectively.5 Plasma donepezil concentrations in patients with Down syndrome were significantly higher than those in healthy volunteers according to the t-test (p < 0.001), and patients with higher concentrations developed adverse reactions more frequently (Figure 1).
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Discussion. Although slightly different doses were given to patients with Down syndrome and healthy volunteers, donepezil concentrations were measured in the same manner. Therefore, such difference would not preclude our interpretation that patients with Down syndrome may be more sensitive to donepezil than others, probably due to differences in its pharmacokinetics. Because both efficacy and toxicity correlated with its plasma concentrations, an optimal regimen is critical for clinical application for these patients. We could not find a relationship between severity of cognitive impairment and plasma donepezil concentration or development of adverse reactions. Our results may partly explain the controversy concerning donepezil therapy for patients with Down syndrome: while some studies reported its efficacy, others stated the serious adverse effects of donepezil.3,4 We emphasize that a dose as low as 3 mg daily should be appropriate for most of these patients and that dose increases to 5 mg daily should be done only if needed, under careful monitoring. The regular maintenance dose (10 mg daily) in the US and European Union is probably too much for patients with Down syndrome.
References
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= patients without adverse reaction; • = patients
with adverse reaction; numbers in parentheses indicate patients or
controls.