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Absorption of Rivastigmine from Different Regions of the Gastrointestinal Tract in Humans

From Clinical Pharmacology, Novartis Pharmaceuticals, East Hanover, New Jersey (Dr. Lee, Dr. Wang, Dr. Sedek) and Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania (Dr. Hossain).

Address for reprints: Lucy Lee, PharmD, Clinical Pharmacology, One Health Plaza, Building 105 2W078F, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936.

	ABSTRACT

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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- = 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.

Key Words: Absorption • metabolism • rivastigmine • ENA713 • NAP226-90 • naso-intestinal intubation • jejunum • ileum • colon • human

Rivastigmine easily penetrates the blood-brain barrier in animal studies (maximal enzyme inhibition 0.5 h following oral administration) and is quickly detected in the cerebrospinal fluid (CSF) in humans following oral administration (t_max ranging from 1.4-3.8 h). The elimination of rivastigmine from CSF, with half-lives ranging from 0.31 to 2.95 hours,³ seems to be in parallel with that from plasma, with a half-life approximately 1 to 2 hours. Although rivastigmine has a short plasma half-life (approximately 1-2 h), its inhibitory effect on AChE seems to be long (10 h).⁴ To maintain adequate plasma levels for a sustained clinical efficacy, rivastigmine has been administered twice a day in Alzheimer's patients. A once-a-day (qd) controlled-release formulation has been considered to improve the ease of administration and compliance.

Rivastigmine is rapidly absorbed after an oral dose, with a t_max ranging from 0.8 to 1.2 hours following oral administration.⁵ Rivastigmine is rapidly and extensively metabolized by its target enzyme via cholinesterase-mediated hydrolysis to the phenolic metabolite, NAP 226-90. Hepatic microsomal enzymes are not involved to any significant extent. The oral bioavailability of rivastigmine increases from approximately 35% at 3 mg to 71.7% at 6 mg.⁶ The extent of absorption and metabolism of rivastigmine at different regions of the gastrointestinal (GI) tract has not been reported.

The effectiveness of a modified-release formulation depends on the absorption characteristics of the gastrointestinal region in which the drug release is intended. Understanding the rate and extent of absorption and metabolism in different GI regions will be of importance for designing a controlled-release formulation. In an attempt to address this concern, the present study was designed to investigate whether differences in rivastigmine absorption and metabolism exist in different regions of the GI tract in humans.

	METHODS

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Clinical Procedures
Study Design
The study employed an open-label design with four-phase treatment periods. Healthy adult subjects received, on separate occasions, a 3-mg dose of a rivastigmine solution orally and via a naso-intestinal tube to the jejunum, ileum, and ascending colon. The intestinal tube was inserted through the nostril, and the location of the tube was determined radiographically prior to dosing. The rivastigmine solution was administered through the tube at approximately 08:00 on 3 study days, and each day involved a different GI site (jejunum, ileum, and ascending colon). The naso-intestinal tube was withdrawn 4 hours after the last dose to the intestine. On the day following tube withdrawal, the subject received a 3-mg dose of a rivastigmine solution, administered daily, at 08:00.

Study Subjects
Eight male and 1 female healthy adult subjects (mean age = 29, mean height = 179 cm, mean weight = 75.8 kg) who satisfied the selection criteria for study entry were enrolled in the study. Each subject gave written informed consent after being advised of the nature and risks of the study. The subjects were confirmed to be in good health by physical examination, medical history, and clinical laboratory tests. Local anesthesia was used in the nasal and oral pharynx to aid in the placement of the naso-intestinal tube and to treat any discomfort arising from the presence of the tubes. Other than this, no other concomitant medication was given from 2 weeks prior to dosing and until all of the final study evaluations were completed. Seven of the 9 subjects completed all study treatments and were included in the evaluation.

Drug Administration
Intubation. On the evening prior to the first treatment phase, a naso-intestinal tube containing a radiopaque marker tip was inserted through the nose into the stomach and allowed to progress through the GI tract via peristalsis. The position of the tube tip was determined radiographically each evening and the following morning prior to each treatment phase. When the tube reached the jejunum, ileum, and ascending colon, a single 3-mg dose of rivastigmine tartrate was administered via the tube. The study drug (3 mg in 1.5 mL) was added to water for a total of 10 mL. The entire 10 mL was administered through the tube to the specified site within the GI tract, followed immediately by an additional 10 mL of water to flush the tube and ensure that the entire dose had been delivered. Consecutive administrations of rivastigmine were given at least 24 hours apart.

Oral. The day after withdrawal of the tube, a dose of rivastigmine was administered orally. The study drug (3 mg in 1.5 mL) was added to water to a total of 10 mL, and the entire 10 mL was swallowed. Immediately after the administration of the dose, an additional 10 mL of water was swallowed.

Food
All subjects fasted for at least 10 hours prior to dosing (08:00) and continued fasting for at least 4 hours afterward. Lunch and dinner were served at 12:00 and 17:30, respectively, and a large snack was served at 21:00. The lunch on dosing days was standardized, and each subject consumed the same lunch on each of the dosing days. No other food was consumed during the treatment periods.

Blood Collection
Blood samples (5 mL) for analysis of rivastigmine and NAP plasma concentrations were collected for 12 hours postdose at the following times: 0 (predose); 10, 20, 30, and 45 minutes; and 1, 1.25, 1.5, 2, 4, 6, 8, and 12 hours postdose. All samples were processed and kept frozen at -20°C pending analysis.

Analytical Procedures
Measurements of rivastigmine and its metabolite in human plasma were performed using a gas chromatographic/mass spectrometric method.⁷ Briefly, 10 mg of internal standards ([²H₆]rivastigmine and [²H₆]NAP 226-90), 4 mL of a sodium hydroxide/sodium carbonate solution (0.7/0.5 mol/L), 4 mL of methyl tert-butyl ether (MTBE), and 100 µL of propionic anhydride were added to each serum sample. Samples were shaken for 15 minutes and centrifuged for 5 minutes, and an aliquot of the aqueous layer was transferred to 1 mL of hydrochloric acid (0.1 mol/L). The tube was shaken for 5 minutes and centrifuged for 5 minutes. The organic phase was removed and replaced with 100 µL of a sodium hydroxide/sodium carbonate solution and 4 mL of MTBE. The sample was shaken for 15 additional minutes, followed by a 5-minute centrifugation. An aliquot was removed from the organic layer, transferred to a 5-mL glass tube, and evaporated under a stream of nitrogen at 40°C. The remaining residue was dissolved in 30 µL of methyl propionate; 3 µL of this solution was injected onto the analytical column for analysis. A linear calibration curve was generated from the standards, and the limit of quantification was 0.2 µg/L for both compounds.

Pharmacokinetic Data Analysis
All subjects who completed at least one treatment period and had a complete pharmacokinetic profile were included in the pharmacokinetic data analysis. For each treatment period, the pharmacokinetic profiles were analyzed by standard noncompartmental methods using the WinNonlin^TM Professional pharmacokinetic software (version 1.5, Pharsight, Palo Alto, CA). Summary statistics were reported for the pharmacokinetic parameters of rivastigmine and NAP 226-90. Individual pharmacokinetic raw data were checked for consistency. Values below the limit of quantitation were set to 0 for pharmacokinetic analysis, and missing values were labeled accordingly and were not included in the analysis. The following PK parameters were calculated:

AUC_0-t (ng•h/mL):

AUC from time zero to the last measurable sampling time point, calculated by the linear trapezoidal method.

AUV_0- (ng•h/mL):

AUC from time zero to time infinity. This is calculated as AUC_{(0 t)} + C_t/_z, where C_t is the concentration at time t, and _z is the terminal elimination rate constant.

C_max (ng/mL):

Maximum (peak) plasma drug concentration after single-dose administration.

t_max (h):

Time to reach C_max following drug administration.

t_1/2 (h):

Elimination half-life determined based on the last three to four data points of the terminal phase.

M/P ratio:

Metabolite to parent AUV_0- ratio.

F_rel = AUC_in/AUC_oral:

Bioavailability of drug delivery to different GI regions relative to oral dose.

Inferential statistical analysis was performed using one-way ANOVA (Microsoft Excel 2002 SP-2). Comparison for the rate of absorption for rivastigmine among the different regions of the GI tract was performed based on C_max values. Comparison for the extent of absorption for rivastigmine among the different regions of the GI tract was performed using F_rel, a measure of relative bioavailability. Comparison for the extent of metabolism for rivastigmine among the different regions of the GI tract was performed based on M/P, a ratio of metabolic to parent exposure. Statistical significance was set a priori at p < 0.05.

	RESULTS

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Of the 9 subjects, only 7 completed the study. Two subjects did not complete the study due to reasons other than intolerable toxicity tolerability. No serious adverse events or deaths were reported during the study. Except for local anesthesia and medication that might have been required to treat adverse events, no medication other than the study drug was given from 2 weeks prior to dosing until after final study evaluations were completed.

Rivastigmine was rapidly absorbed following oral administration and site-specific delivery to different regions of the GI tract (jejunum, ileum, and ascending colon) (Figure 1, Table I). The C_max values for oral dose and delivery to different GI regions are similar (p = 0.25). The time to peak rivastigmine concentration appeared to be shorter for direct GI delivery (mean t_max ranged from 0.40-0.58 h) than for the oral dose (0.87 h), which reflects the time needed for stomach emptying after an oral dose. Compared with oral administration (mean AUV_0- = 21 ng•h/mL), delivery of rivastigmine directly into the ileum, jejunum, and ascending colon did not substantially change the extent of rivastigmine bioavailability (p = 0.82). The relative bioavailability of rivastigmine from all three regions of the GI tract to oral dose was comparable (p = 0.52), ranging from 85.3% to 112.5% (n = 7). The half-life was 1.01 ± 0.17 hours and 2.53 ± 0.42 hours for the parent drug and metabolite, respectively. The extent of NAP 226-90 formed was not different among different regions of the GI tract, including oral dose (p = 0.76) (Figure 2).

View larger version (23K): [in this window] [in a new window]   Figure 1. Mean plasma concentration-time profile of rivastigmine (ENA 713) and metabolite (NAP 226-90) following the 3-mg single dose. Black = ENA 713; Gray = NAP 226-90.

View larger version (13K): [in this window] [in a new window]   Figure 2. Comparison of metabolite (NAP 226-90) to parent (ENA 713) AUV0- ratio following the 3-mg single dose of rivastigmine.

	DISCUSSION

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Absorption depends on the interaction between the physiochemical properties of the drug and the physiological variables that may be unique to each region of the GI tract. Factors that may contribute to the differences in the rate and extent of absorption among the different regions of the GI tract include the extent of presystemic metabolism, efflux, and "absorption window" if a carrier-mediated transport is involved; regional pH; GI motility; and luminal contents.⁸ Rivastigmine is a small water-soluble compound (MW 250), with a octanol/water coefficient of 3 and pKa of 8.85. Human studies have shown that the oral absorption of rivastigmine is nearly complete, whereas the oral bioavailability is only 30% to 40%, suggesting a substantial first-pass metabolism.⁹

A number of techniques are available to study the absorption of drugs in different regions of the GI tract, such as the use of an externally activated drug delivery system, InteliSite capsules¹⁰; the use of a different intubation method for studying the intestinal permeability of a compound¹¹; and the naso-intestinal intubation method used in the current study. The intestinal perfusion technique allows measurement of drug permeability across the intestinal membrane in vivo. However, the duration of the study is normally short, and tube placement may affect gastric and intestinal motility, which may affect the absorption characteristics of the GI tract. The InteliSite capsules are less invasive, but special expertise is required to activate the release of the capsule in a specific region of the GI tract, and an accurate placement of the capsule might be challenging because of a lack of anatomical landmarks to separate different regions. Other than the risk related to using radioactive labels, the potential for mechanical obstruction in the GI tract by the capsule is also a concern. Although each technique has its own limitations, in general, these techniques have proven to be useful in understanding the absorption characteristics of a drug in different regions of the GI tract.

This current study was conducted to determine and compare the absorption profile of rivastigmine when administered to various regions of the GI tract by using a naso-intestinal intubation technique. An accurate placement and drug delivery can be easily achieved based on the length of the tube inserted. The tube is taken out once the drug solution is delivered, which allows drug absorption to take place at normal physiological conditions. The results demonstrate that rivastigmine was rapidly and equally well absorbed following specific delivery to the upper and lower regions of the small intestine and from the ascending colon. The time to peak concentration was similar among the three regions, averaging 0.44 to 0.58 hours, but was all shorter than the time to peak concentration after oral dosing (0.87 h). Because rivastigmine is readily absorbed from all GI regions when delivered directly, a longer t_max for oral dosing suggests that no or little rivastigmine was absorbed from the stomach, and the difference in t_max between the two dosing routes represents approximately the stomach-emptying time (0.29-0.43 h for rivastigmine), which is similar to the physiological stomach-emptying time reported in the literature.¹² A similar rate and extent of absorption among different regions suggest that the absorption of rivastigmine is probably not selective along the GI tract at the dose level studied.

Early studies have shown that rivastigmine undergoes substantial first-pass metabolism. The major metabolite formed in humans is NAP 226-90, which was measured in the present study. As shown in Figure 1 and Table 1, the concentrations of NAP 226-90 were similar among different GI regions, as were the metabolite to parent drug concentration ratios, suggesting that GI metabolism of rivastigmine to its major metabolite, NAP 226-90, was similar in different segments of the GI tract. Since cholinesterases, both AChE and BChE, are the primary enzymes catalyzing the metabolism of rivastigmine, the current study results indicate that the distribution and metabolic capacity of cholinesterases is probably equally distributed among the GI regions tested. However, since the metabolism of rivastigmine at the 3-mg dose is near to the saturation range,⁶ a lower dose of rivastigmine should be tested before a final conclusion can be made.

In conclusion, the absorption of rivastigmine was rapid following either an oral dose or a specific delivery to different GI regions (jejunum, ileum, and ascending colon) in humans. No difference for the rate and extent of rivastigmine absorption and metabolism was observed among the three regions of the GI tract studied.

	FOOTNOTES

 
DOI: 10.1177/0091270004265645

Submitted for publication January 6, 2004;

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