Titre du document / Document title

Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses

Auteur(s) / Author(s)

NAGY Christa F. ⁽¹⁾ ; KUMAR Dinesh ⁽²⁾ ; PERDOMO Carlos A. ⁽²⁾ ; WASON Suman ⁽³⁾ ; CULLEN Edward I. ⁽¹⁾ ; PRATT Raymond D. ⁽⁴⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Clinical Pharmacology, Eisai Medical Research Inc., Ridgefield Park, NJ, ETATS-UNIS
⁽²⁾ Biometrics Biostatistics, Eisai Medical Research Inc., Ridgefield Park, NJ, ETATS-UNIS
⁽³⁾ Clinical Research, Eisai Medical Research Inc., Ridgefield Park, NJ, ETATS-UNIS
⁽⁴⁾ Phoenix International Life Sciences Inc., Cincinnati, OH, ETATS-UNIS

Résumé / Abstract

Aim This study evaluated the safety and pharmacokinetics (PK) of donepezil HCI and sertraline HCl when administered separately and in combination. Methods This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of ≥3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). Results A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/ stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (<12%) but statistically significant (P = 0.02) increase in donepezil C_max was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the t_max or AUC_{0-24 h} of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone. Conclusions The co-administration of once-daily oral donepezil HCl 5 mg for 15 days and once-daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed.

Revue / Journal Title

British journal of clinical pharmacology. Supplement   ISSN 0264-3774 

Source / Source

2004, vol. 58, n^o 1 (62 p.)  [Document : 9 p.] (39 ref.), pp. 25-33 [9 page(s) (article)]

Langue / Language

Anglais

Editeur / Publisher

Blackwell, Oxford, ROYAUME-UNI  (1976) (Revue)

Mots-clés anglais / English Keywords

Neurotransmitter ; Selective serotonin reuptake inhibitor ; Serotonin ; Reuptake inhibitor ; Piperidine derivatives ; Enzyme inhibitor ; Anticholinesterase agent ; Enzyme ; Hydrolases ; Esterases ; Carboxylic ester hydrolases ; Acetylcholinesterase ; Antidepressant agent ; Nootropic agent ; Antialzheimer agent ; Psychotropic ; Drug interaction ; Oral administration ; Multiple dose ; Safety ; Toxicity ; Pharmacokinetics ; Human ; Healthy subject ; Sertraline ; Donepezil ; Drug combination ;

Mots-clés français / French Keywords

Naphtylamine dérivé ; Neurotransmetteur ; Inhibiteur sélectif recapture sérotonine ; Sérotonine ; Inhibiteur recapture ; Pipéridine dérivé ; Inhibiteur enzyme ; Anticholinestérasique ; Enzyme ; Hydrolases ; Esterases ; Carboxylic ester hydrolases ; Acetylcholinesterase ; Antidépresseur ; Nootrope ; Antialzheimer ; Psychotrope ; Interaction médicamenteuse ; Voie orale ; Dose répétée ; Sécurité ; Toxicité ; Pharmacocinétique ; Homme ; Individu sain ; Sertraline ; Donépézil ; Association médicamenteuse ;

Mots-clés espagnols / Spanish Keywords

Neurotransmisor ; Inhibidor selectivo recaptura serotonin ; Serotonina ; Inhibidor recaptura ; Piperidina derivado ; Inhibidor enzima ; Anticolinesterasa agente ; Enzima ; Hydrolases ; Esterases ; Carboxylic ester hydrolases ; Acetylcholinesterase ; Antidepresor ; Nootropo ; Antialzheimer ; Psicotropo ; Interacción medicamentosa ; Vía oral ; Dosis múltiple ; Seguridad ; Toxicidad ; Farmacocinética ; Hombre ; Individuo sano ; Sertralina ; Donepezilo ; Asociación medicamentosa ;

Localisation / Location

INIST-CNRS, Cote INIST : 16791 S, 35400012053634.0040