British Journal of Clinical Pharmacology

Jackson, Stephen; Ham, Richard J.; Wilkinson, David

doi: 10.1111/j.1365-2125.2004.01848.xpmid: 15496217

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side‐effects and general tolerability concerns, including hepatotoxicity. Side‐effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug–drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single‐ and multiple‐dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug–drug interactions. The incidence of weight loss is very similar between donepezil‐ and placebo‐treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day−1 or switching to morning dosing can reduce these events to the levels of placebo‐treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Reyes, Josephine F.; Vargas, Ramon; Kumar, Dinesh; Cullen, Edward I.; Perdomo, Carlos A.; Pratt, Raymond D.

doi: 10.1111/j.1365-2125.2004.01802.xpmid: 15496218

Aims To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady‐state, multiple‐dose conditions. Methods In this single‐centre, multiple‐dose, open‐label study, patients with impaired hepatic function (Child–Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment‐emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study. Results A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in Tmax, while t½ and AUC0–∞ were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC0−24 h, Cmax, t½, CSS, and RA were significantly increased in hepatically impaired patients compared with healthy controls. AUC0−24 h increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs. Conclusions The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child–Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age‐matched volunteers.

Nagy, Christa F.; Kumar, Dinesh; Cullen, Edward I.; Bolton, W. Kline; Marbury, Thomas C.; Gutierrez, Maria J.; Hutman, H. Wayne; Pratt, Raymond D.

doi: 10.1111/j.1365-2125.2004.01803.xpmid: 15496219

Aims To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single‐dose and multiple‐dose phases. Methods This open‐label study enrolled subjects with moderate renal impairment (creatinine clearance (CLCr) 17–33 ml min−1 1.73 m−2 body surface area) and age, weight and sex‐matched healthy controls. A single‐dose (5 mg donepezil) phase was followed by a 23‐day multiple dose (5 mg day−1 donepezil) steady‐state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose. Results Thirty‐six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (Cmax 5.17 ± 0.36 and 6.07 ± 0.49 ng ml−1; AUC0−24 76.05 ± 5.54 and 77.45 ± 4.49 ng·h ml−1; mean maximum percentage inhibition (Imax) red blood cell (RBC) AChE activity 32.07 ± 2.00 and 31.69 ± 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady‐state conditions did not differ between renally impaired and healthy subjects (CSS 20.83 ± 1.78 and 18.38 ± 1.52 ng ml−1; AUC0−24 500.0 ± 42.8 and 441.1 ± 36.4 ng·h ml−1; degree of accumulation (RA) 6.98 ± 0.59 and 5.94 ± 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition (ISS) RBC AChE activity 65.11 ± 2.52 and 60.62 ± 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 ± 1.96 and 20.23 ± 0.64, respectively). Donepezil was well tolerated by both groups. Conclusions These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.

Nagy, Christa F.; Kumar, Dinesh; Perdomo, Carlos A.; Wason, Suman; Cullen, Edward I.; Pratt, Raymond D.

doi: 10.1111/j.1365-2125.2004.01801.xpmid: 15496220

Aim This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl 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 Cmax 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 tmax or AUC0−24 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.

Ravic, Miroslav; Warrington, Steve; Boyce, Malcolm; Dunn, Kate; Johnston, Atholl

doi: 10.1111/j.1365-2125.2004.01800.xpmid: 15496221

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 AUC0–tn, AUC0–∞, t½ and tmax. Cmax 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.

Okereke, Chukwuemeka S.; Kirby, Louis; Kumar, Dinesh; Cullen, Edward I.; Pratt, Raymond D.; Hahne, William A.

doi: 10.1111/j.1365-2125.2004.01799.xpmid: 15496222

Aim The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double‐blind, crossover study investigated the safety of, and possible drug–drug interaction between, donepezil HCl and levodopa/carbidopa. Methods Twenty‐five patients with PD who were taking physician‐optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4–8 h) were administered once‐daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty‐six healthy matched controls received open‐label donepezil HCl only, for a single 15‐day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (Cmax), time at which Cmax is attained (tmax), plasma drug concentration at steady state (Css), and area under the drug concentration–time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. Results The mean age of all subjects was 72.6 ± 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC0−12 h= 281.6 ± 17.6 and 268.6 ± 19.9 ng·h ml−1, respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC0−8 h= 921.8 ± 160 and 821.8 ± 113 ng·h ml−1, respectively). Four hours after administration of donepezil HCl in PD patients, AUC0−4 h, Cmax and Css of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only Cmax and tmax were observed to change compared with when PD patients received placebo (mean Cmax = 2652 ± 429 and 2077 ± 276 ng ml−1, respectively; mean tmax = 1.7 ± 0.4 and 2.9 ± 0.5 h, respectively; P≤ 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. Conclusions No clinically significant drug–drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co‐administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

Reyes, Josephine F.; Preskorn, Sheldon H.; Khan, Ahsan; Kumar, Dinesh; Cullen, Edward I.; Perdomo, Carlos A.; Pratt, Raymond D.

doi: 10.1111/j.1365-2125.2004.01817.xpmid: 15496223

Aim This open‐label, multiple‐dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs. Methods Sixteen male patients with schizophrenia, who were receiving stable, physician‐optimized risperidone (1–4 mg twice daily), and 15 healthy age‐ and weight‐matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician‐optimized dose of risperidone throughout the study. Pharmacokinetic parameters (Cmax, tmax and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7). Results The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC0−24 h = 329.0 ± 17.2 ng·h ml−1) and controls taking donepezil HCl alone (AUC0−24 h = 354.7 ± 28.2 ng·h ml−1). Pharmacokinetic parameters for risperidone and 9‐OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC0−12 h standardized by dose: risperidone = 59.6 ± 16.3 ng·h ml−1 at day 0, 56.0 ± 15.8 ng·h ml−1 at day 7; 9‐OH risperidone = 162.1 ± 19.2 ng·h ml−1 at day 0, 163.3 ± 15.0 ng·h ml−1 at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment‐emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side‐effects following donepezil administration. Conclusions These results suggest that once‐daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.