Similar rivastigmine pharmacokinetics and pharmacodynamics in Japanese and white healthy participants following the application of novel rivastigmine patch.

The pharmacokinetics and pharmacodynamics of rivastigmine were compared in Japanese and white healthy participants who were given ascending single doses of the novel rivastigmine transdermal patch. Rivastigmine patch strengths were 4.6 mg/24 h (5 cm2, 9 mg rivastigmine loaded dose), 9.5 mg/24 h (10 cm2, 18 mg), and 13.3 mg/24 h (15 cm2, 27 mg) (per label) or 7.0 mg/24 h (7.5 cm2, 13.5 mg) as a fall-back dose. No relevant ethnic differences in the noncompartmental pharmacokinetics (parent and metabolite NAP226-90) and pharmacodynamics (plasma BuChE activity) of the rivastigmine patch were observed between Japanese and whites. However, drug exposure was slightly higher and inhibition of BuChE slightly more pronounced in Japanese participants than in whites, which was attributed to the lower body weight (ca. 11% less on average) of Japanese participants. Treatments were similarly well tolerated in both ethnic groups. In conclusion, no relevant ethnic differences in the intrinsic disposition or effects of rivastigmine delivered via transdermal route are expected between Japanese and white patients. The possible effect of body weight on drug exposure suggests that special attention should be paid to patients with very low body weight during up-titration.

Steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease not affected by co-administration of memantine: an open-label, crossover, single-centre study.

BACKGROUND AND OBJECTIVE: It has been shown that combining memantine and a cholinesterase inhibitor, which each affect different neurotransmitter systems, may offer further improvements in efficacy over either treatment alone in patients with Alzheimer's disease. The present study was conducted to determine if memantine has any effects on the steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease. METHODS: Rivastigmine-treated Alzheimer's disease patients who had been maintained on a fixed regimen of twice-daily rivastigmine for >or=2 months were eligible to enter the study. Sixteen patients (seven males and nine females, age range 64-88 years, weight range 51.8-104 kg) were enrolled in this open-label, crossover study, which consisted of a 28-day screening period, a 36-hour baseline period, and a 35-day combination treatment phase. The patients spent the baseline period and day 35 at the study centre, where plasma samples for pharmacokinetic evaluation were taken at specified time intervals over a 10-hour time period. In addition, 10-hour (evening pre-dose) memantine plasma samples were taken on days 21, 34 and 35. RESULTS: The combination of memantine (10 mg twice daily) with rivastigmine (1.5-6 mg twice daily) was safe and well tolerated. At each dose level of rivastigmine, the area under the concentration-time curve (AUC) values of rivastigmine and its metabolite as well as the metabolite-to-parent AUC ratios were unaffected by co-administration of memantine, confirming the absence of a meaningful pharmacokinetic drug-drug interaction. CONCLUSION: Under the study conditions, the extent of systemic exposure to rivastigmine and its metabolite NAP226-90 at steady state did not appear to be affected by concomitant administration of memantine.

Pharmacokinetics of a rivastigmine transdermal patch formulation in healthy volunteers: relative effects of body site application.

A patch formulation of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, is under development. The current objective was to evaluate the pharmacokinetic profile and patch adhesiveness following application at the upper back, chest, abdomen, thigh, and upper arm. In a single-dose, open-label, crossover study with 40 (42.5% men) healthy subjects, a 10-cm(2) patch containing 18 mg rivastigmine was applied to each body site. Median t(max) was 16 hours for all sites except the thigh (22 hours). Exposure levels and C(max) were highest at the upper back, chest, and upper arm sites. Adhesiveness was greatest when applied to the thigh, followed by the abdomen, upper arm, chest, and upper back, although no statistically significant correlations with pharmacokinetic parameters were found, except at the chest (P=.02). Pharmacokinetic profiles and adhesiveness of the upper back, chest, and upper arm, coupled with low rates of erythema at these sites, suggest their suitability for clinical use.

Dose-proportional pharmacokinetics of d-threo-methylphenidate after a repeated-action release dosage form.

A bimodal extended-release formulation of d-methylphenidate (d-MPH) has been developed to enable fast onset of action and once-daily administration in patients with attention deficit hyperactivity disorder. The authors studied the dose proportionality of extended-release d-MPH pharmacokinetics. Twenty-five healthy adult volunteers received 5, 10, 20, 30, and 40 mg d-MPH in a crossover study with 7 days between doses. All doses were well tolerated. Dose proportionality was shown for all dose-dependent pharmacokinetic parameters. Geometric means (%gCV) for the first Cmax peak, Cmax0-4, were 3.25 (29.0%), 6.05 (27.1%), 12.6 (31.9%), 18.5 (31.9%), and 25.2 ng/mL (29.3%) for d-MPH 5, 10, 20, 30, and 40 mg, respectively. Geometric means (%gCV) for Cmax4-10 were 3.18 (27.5%), 5.84 (27.7%), 12.5 (31.7%), 17.7 (31.6%), and 23.6 ng/mL (29.0%), respectively. Geometric means for AUC(0-infinity) were 24.3 (30.7%), 45.9 (30.2%), 96.4 (35.5%), 144 (33.3%), and 195 ng x h/mL (30.9%), respectively. The pharmacokinetics of once-daily extended-release d-MPH are proportional to the dose.

Absorption of rivastigmine from different regions of the gastrointestinal tract in humans.

The objective of this study was to evaluate the rate and extent of absorption and metabolism of rivastigmine (Exelon), ENA 713) after site-specific delivery of the drug in the gastrointestinal (GI) tract using a naso-intestinal intubation technique. Healthy adult subjects (n = 7) received, on four separate occasions, a 3-mg dose of a rivastigmine solution (2 mg/mL) orally and via a naso-intestinal tube to three GI sites (jejunum, ileum, and ascending colon). On each of the 3 treatment days for regional GI dosing, the tube was progressed to each of the three GI sites, which was determined by a radiographical technique prior to dosing. On the fourth day, following tube withdrawal, the subject received a 3-mg oral dose of a rivastigmine solution. Plasma samples were obtained at different multiple time points, and the plasma concentrations of rivastigmine and its metabolite, NAP 226-90, were determined using a gas chromatography/mass spectrometry (GC/MS) method. Rivastigmine was rapidly absorbed following both oral administration and site-specific delivery to different regions of the GI tract (jejunum, ileum, and ascending colon). Compared with oral administration (AUV(0- infinity ) = 21 ng*h/mL, C(max) = 12.8 ng/mL, and t(max) = 0.87 h), delivery of the drug directly into the ileum, jejunum, and ascending colon did not change the extent of absorption, but the time to peak concentration appeared to be smaller (mean t(max) ranged from 0.4-0.6 h, with no change in C(max)). The relative bioavailability of rivastigmine from all three regions of the GI tract was comparable to that following oral administration. The metabolite levels (AUC, C(max)) were also similar among the three different regions of the GI tract when compared to the oral dose. It was concluded that rivastigmine is rapidly and equally well absorbed following an oral dose and after specific delivery to different regions of the small intestine and ascending colon. GI metabolism of rivastigmine to its major metabolite, NAP 226-90, occurs to a similar extent in different segments of the GI tract.

In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers.

PURPOSE: The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. METHODS: The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall Cmax, tmax and AUC values, as well as the Cmax, tmax and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. RESULTS: All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at approximately 2 and approximately 6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to approximately 2 h, and a somewhat slower second absorption between approximately 3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall Cmax and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second Cmax and a higher trough concentration between peaks, as well as similar overall plasma AUC. CONCLUSIONS: Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared not to affect the overall bioavailability of MPH in humans.

Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type.

OBJECTIVE: To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg. DESIGN AND SETTING: Randomised, two-period crossover, single-centre, non-blinded, inpatient study. PATIENTS AND PARTICIPANTS: Eleven patients (five females and six males) with mean age 69.5 years. METHODS: The 6 mg oral dose was compared with a 2 mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method. RESULTS: Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration. CONCLUSION: A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6 mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics..