IngentaConnect Repeated dosing with donepezil does not affect the safety, tolera...

Authors: Ravic, Miroslav; Warrington, Steve¹; Boyce, Malcolm¹; Dunn, Kate¹; Johnston, Atholl²

Source: British Journal of Clinical Pharmacology, Volume 58, Supplement 1, November 2004 , pp. 34-40(7)

Abstract:

Aim

To investigate the effects of donepezil at steady state on the safety, tolerability and pharmacokinetics of a single dose of thioridazine, in healthy subjects. Methods

An open, two-way, balanced crossover study, in 12 subjects (six men and six women) aged 19-41 years. During both treatment periods, subjects received a single oral dose of 50 mg thioridazine; in one period the thioridazine was given alone, and in the other period it was given together with the last of 15 daily, oral doses of donepezil 5 mg. The `washout' periods were 1 week when thioridazine was given first, and 2 weeks when thioridazine was given last. Plasma concentrations of thioridazine were measured after each dose, and pharmacokinetic parameters were determined. Interactions were tested by using an equivalence analysis in which thioridazine was the `Reference' and thioridazine + donepezil the `Test' regimen. Safety and tolerability were monitored. Results

Donepezil had no marked effect on the pharmacokinetics of thioridazine, as judged by the equivalence analysis of AUC_0-tn, AUC_0-∞, t_½ and t_max. C_max was very similar in the `Test' and `Reference' regimens, but the confidence intervals were too wide to confirm equivalence. Donepezil was well tolerated, whereas thioridazine was associated with light-headedness, tiredness and postural hypotension, irrespective of whether or not donepezil was given concurrently. Conclusions

Repeated dosing with donepezil, 5 mg daily for 2 weeks, had no significant effect on the safety, tolerability or pharmacokinetics of thioridazine. Thioridazine was poorly tolerated.

Keywords: acetylcholinesterase inhibitor; Alzheimer's disease; donepezil; drug-drug interactions; pharmacokinetics; thioridazine

Document Type: Research article

DOI: 10.1111/j.1365-2125.2004.01800.x

Affiliations: 1: Hammersmith Medicines Research, Central Middlesex Hospital, London, UK and 2: Analytical Unit, The Medical School, St George's Hospital, London, UK

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Repeated dosing with donepezil does not affect the safety, tolerability or pharmacokinetics of single-dose thioridazine in young volunteers