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BRIEF REPORTS/PHARMACOKINETICS |
dek, MD, PhD
From Novartis Pharma AG, Basel, Switzerland (Dr Lefèvre, Mrs Kiese, Dr Appel-Dingemanse); Novartis Pharma SAS, Rueil-Malmaison, France (Mrs Pommier); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Sdek, Dr Huang, Dr Ho); and MDS Pharma Services, Phoenix, Arizona (Dr Allison).
Address for correspondence: Dr G Lefèvre, Novartis Pharma AG, Exploratory Development, WSJ-210.4.25, CH-4002 Basel, Switzerland; e-mail: gilbert.lefevre{at}novartis.com.
Key Words: Alzheimer's disease • Exelon • rivastigmine • pharmacokinetics • transdermal patch
Alzheimer's disease (AD) is the most common cause of progressive dementia in people of advanced age. Although the etiology of the disease is not clearly established, several causes for the development of AD have been proposed, one of which is the cholinergic hypothesis. Acetylcholine (ACh) is the primary neurotransmitter that facilitates learning and improves attention.1,2 Its deficiency, which leads to dysfunctional cholinergic signaling in the cortex and hippocampus, is considered the cause of cognitive impairment. Among the different types of drugs used to modify cholinergic neurotransmission, cholinesterase inhibitors (ChEIs) form the mainstay of treatment for mild to moderate AD.3-8
Rivastigmine, a ChEI with established efficacy in the treatment of AD,9-11 and more recently for Parkinson's disease dementia (PDD), has a dual, pseudo-irreversible inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). This dual inhibitory action has been reported to have additional clinical benefits.12,13 The drug easily penetrates the blood-brain barrier and specifically targets AChE and BuChE in the brain, particularly the cortex and hippocampus.14,15 Consequently, ACh hydrolysis is inhibited in the presence of the drug, and levels of ACh are elevated in brain synapses. Rivastigmine has been shown to improve or maintain cognitive function, activities of daily living and behavior, as well as overall (global) dementia symptoms in patients with mild to moderate AD and PDD.13
Oral rivastigmine is available as capsules (1.5, 3.0, 4.5, and 6.0 mg) and a bioequivalent oral solution (2 mg/mL), administered twice daily. Most commonly reported adverse events involve the gastrointestinal system (nausea, vomiting, diarrhea) and are consistent with the cholinomimetic effects of rivastigmine. An analysis of cholinesterase inhibitors indicated that the incidence of adverse effects depends on the degree and duration of enzyme inhibition and on the extent of daily fluctuations in enzyme activity.16 It is believed that reducing daily fluctuations in the rivastigmine pharmacokinetic (PK) profile will lead to a decrease in fluctuations in the extent of enzyme inhibition, improving overall tolerability while maintaining efficacy throughout the day. To achieve this PK profile, a novel rivastigmine transdermal delivery system has been developed. The rivastigmine patch was recently approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate AD and PDD in the United States, and by the European Medicines Agency (EMEA) for the treatment of mild to moderate AD in Europe.
Transdermal patches offer many advantages over conventional oral medications, including smooth and continuous drug delivery, reduced Cmax, and steadier systemic drug levels. This may improve the tolerability profile, allowing easier access to optimal therapeutic doses. The rivastigmine patch is applied once daily, potentially improving convenience and treatment compliance. The current objective was to evaluate the relative bioavailability of rivastigmine and its metabolite in healthy subjects following single 24-h application of the 9.5 mg/24-h rivastigmine patch (10 cm2; 18 mg dose load), compared with a 3 mg single dose of reference oral solution.
METHODS
Subjects and Clinical Protocol
This was a single-center, randomized, open-label, 2-period crossover, single-dose study. It was conducted at MDS Pharma Services, Phoenix, Ariz, in accordance with the World Medical Association's Declaration of Helsinki, Venice, Hong Kong, and Somerset West amendments 1983, 1989, and 1996,17 and Good Clinical Practice.18 Ethical approval of the study protocol, consent form, and volunteer information document was granted by MDS Pharma Services Institutional Review Board, Lincoln, Nebraska.
Thirty subjects were to be randomized to 1 of 2 study sequences. Each treatment period consisted of either a 24-h single application of a 9.5 mg/24-h (10 cm2; 18 mg dose load) rivastigmine (Exelon, Novartis) patch on the upper scapular region of the back, or a single 3 mg dose of oral solution. There was a 72-h washout interval between the 2 treatment periods. Each subject underwent a 28-day screening period, a 12-h baseline assessment prior to each treatment period, a 6-day domiciled stay during the completion of the 2 treatment periods in sequence, and a completion evaluation following the last PK sample.
On dosing days, subjects were administered the assigned dose following an overnight fast and continued to fast up to 2 h postdose. Standard breakfast, lunch, and dinner meals were served at 2, 5, and 9.5 h postdose, respectively. Subjects were confined to the study site from day -1 (baseline) to study completion. Subjects were instructed not to consume alcohol, food, or beverages containing caffeine or other xanthines 48 h prior to dosing and while domiciled.
Drug Assay and Pharmacokinetic Evaluation
Blood samples (3 mL) were collected to characterize the plasma PK and bioavailability of rivastigmine and its metabolite NAP226-90 (pharmacologically inactive) following patch and oral solution administrations. Blood was taken by direct venipuncture into heparinized tubes, and immediately transferred to a prechilled polypropylene physostigmine-containing tube (10 µL of a 0.01 molar physostigmine solution per 1 mL blood) to inhibit any ex vivo enzymatic breakdown of the parent compound and its metabolite. The whole blood sample was centrifuged at 2000 rpm (
800 g), 3° to 5°C, for 15 min, and the harvested plasma was transferred to a polypropylene cryo-tube and stored frozen at -20°C pending analysis. For the oral solution arm, samples were collected at 0 (predose), 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, and 24 h postdose. For the patch arm, samples were collected at 0 (predose), 3, 6, 8, 12, 16, 24, 26, 28, 32, 36, and 40 h postapplication.
Plasma concentrations of rivastigmine and NAP226-90 were assessed at Novartis, Rueil-Malmaison, France, using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method with atmospheric pressure chemical ionization mode (APCI).19 The limit of quantification (LOQ) was 0.2 ng/mL for both compounds using 0.5 mL of plasma sample. During the within-study validation, the mean accuracy (CV%) for rivastigmine was 101% (7.1%) at 0.4 ng/mL, 100% (3.1%) at 5.0 ng/mL, and 102% (3.4%) at 25 ng/mL. For NAP226-90, the mean accuracy (CV%) was 99% (10.3%) at 0.4 ng/mL, 101% (7.6%) at 5.0 ng/mL, and 102% (8.1%) at 25 ng/mL.
Pharmacokinetic parameters were derived using noncompartmental methods (WinNonlin Professional Ver. 4.0.1, Pharsight Corp., Calif): peak concentration (Cmax), time to reach Cmax (tmax); elimination half-life from plasma (t
); and area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24h), or time 0 to last time point (AUClast), or time 0 to infinity (AUC
). Since AUC could be characterized for every subject based on measured concentration data, only AUC data are presented in this paper. Relative rivastigmine bioavailability was assessed using oral solution as the reference treatment.
Patch Adhesion and Residual Drug Content in Worn Patches
Patch adhesion was assessed at 6, 12, and 24 h postapplication. Worn patches were preserved and sent to the manufacturer, Lohmann Therapie-System AG in Germany, for residual drug analysis. Worn patches were stored between 2° to 8°C until they were analyzed. Each patch was transferred into a suitable Erlenmeyer flask, and a solvent mixture consisting of methanol/ethylacetate/diethylamine (70:30:0.4 V/V/V) was added. This was stirred with a frequency of about 200 min-1 for at least 16 h. An aliquot volume of the sample solution was then centrifuged for at least 10 min at about 10 000 min-1 (eg, in 2.0 mL micro test tubes with safety lid lock, Fa. Eppendorf). An aliquot of the supernatant solution was analyzed using HPLC/UV.
Tolerability and Safety Analysis
Safety and tolerability assessments included the monitoring and recording of all adverse events and of concomitant medications, regular checks of routine blood biochemistry, hematology and urinalysis, ECG recordings, measurements of vital signs, and physical examination.
Sample Size Calculation and Statistical Analysis
A study population of 30 subjects was required to ensure 80% power to detect a 35% difference (
= 0.05, 2-sided) in bioavailability between the reference (oral) and test formulation (patch).
Inferential statistics on the log-transformed PK parameters (AUClast, AUC, and Cmax) were performed using the 3 mg oral dose as reference. A linear mixed-effect model, including treatment, period, and sequence as fixed factors and subject-within-sequence and error as random factors, was used to fit the log-transformed PK parameters. Ninety percent confidence intervals (CI) and point estimates for the geometric mean ratios of PK parameters were calculated. For tmax only untransformed data were analyzed by Wilcoxon's signed-rank test.
RESULTS
Subject Disposition and Demographics
Thirty healthy elderly men (n = 13) and women (n = 17) completed the study according to the protocol. Their mean (±SD) age was 67.7 years (±6.31; range, 59-85) and body weight was 73.6 kg (±11.8; range, 56.4-99.8). Although the study population reflected the intended population, 12 subjects were younger than 65 (range, 59-64) and were not strictly "elderly" with respect to standard guidance.
All subjects were in good general health with Mini-Mental State Examination (MMSE) scores >27 points. Except for 1 subject who was given ibuprofen once (800 mg) for hip pain, none of the subjects were taking concomitant medication at screening or baseline assessment, and no concomitant medication was administered throughout the study.
Pharmacokinetics
The arithmetic mean plasma concentration-time profiles for rivastigmine and its metabolite NAP226-90 are shown in Figure 1. Corresponding PK parameters are summarized in Table 1.
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After oral administration of 3 mg rivastigmine solution, rivastigmine was rapidly absorbed and reached a Cmax of 7.63 ± 6.60 ng/mL at a median tmax of 1 h (range, 0.75-1.50 h). AUC was 22.6 ± 26.4 ng·h/mL. After the application of the 9.5 mg/24-h rivastigmine patch, rivastigmine concentration rose much more slowly and reached a plateau between 8 and 26 h (median tmax = 14.1 h) with a Cmax of 5.84 ± 4.43 ng/mL, while AUC was 118 ± 92.4 ng·h/mL. Therefore, the absolute rivastigmine total exposure (ie, AUC) was, overall, 5.2-fold higher with the 9.5 mg/24-h patch compared with 3 mg oral solution, while Cmax after patch administration was 20% lower than that following the 3 mg oral dose. Considering the same parameters normalized by dose (as determined from the measurement of the amount of drug remaining in the patch after use) per kg body weight, the patch/solution ratio (geometric mean of individual ratios) was 2.50 for AUC and 0.31 for Cmax. The mean terminal elimination half-life of rivastigmine was 1.45 ± 0.43 h after administration of the oral solution and 3.02 ± 0.83 h after patch application.
The relative difference between maximum (Cmax) and minimum (at 12 h for oral and 24 h for patch) plasma concentrations was markedly lower with the patch than with the oral solution. Rivastigmine minimum concentrations were approximately 70% of Cmax (5.84 ng/mL) at 24 h after the patch application, in contrast to oral dosing for which concentrations fell from 7.63 ng/mL (Cmax) to virtually 0, 12 h postdose.
Intersubject variability in Cmax and AUC parameters for rivastigmine, as characterized by coefficients of variation (CVs), was 87% and 117%, respectively, after the oral solution, and 76% and 78%, respectively, after the patch. Considering the same parameters (Cmax and AUC) normalized by dose per kg body weight, the CV was markedly lower following patch administration (43% and 46%, respectively), compared with after the oral dose (74% and 102%, respectively).
After the 3 mg oral solution dose, the metabolite NAP226-90 reached a maximum concentration of 6.59 ± 1.96 ng/mL at a median tmax of 1.5 h (range, 0.75-3.0 h). Following application of the 9.5 mg/24-h patch, a plateau concentration was reached between 8 and 28 h (median, 16 h) with a Cmax of 2.87 ± 1.42 ng/mL. The mean (±SD) metabolite-to-parent AUC ratio for the oral solution (3.49 ± 3.44, CV = 99%) was notably higher than that for the patch formulation (0.67 ± 0.19, CV = 28%). Intersubject variabilities in Cmax and AUC parameters for NAP226-90 were 30% and 26%, respectively, after the oral dose, and 49% and 47%, respectively, after the patch. When considering the same parameters normalized by dose per kg body weight, the variability was lower: 25% and 17%, versus 27% and 24%, respectively, and of similar magnitude for the oral and patch formulations. The mean terminal elimination half-life of NAP226-90 was 3.02 ± 0.52 h after administration of the oral solution, and 4.80 ± 0.91 h after patch application.
Patch Adhesion and Drug Residual in Worn Patches
Patch adhesion was good; there were no significant patch adhesion problems that could have had an impact on the results of this study. Average rivastigmine residue in the patch after 24 h was 9.85 ± 1.76 mg. The amount of drug delivered from each patch was used in the dose-normalization of the corresponding individual PK estimates.
Safety and Tolerability
Rivastigmine patch and oral solution were well tolerated. No serious adverse events were reported. There were no clinically significant changes in vital signs or ECG changes from dosing right through to and including the end of study evaluation.
Adverse events reported after either patch or oral solution administration were most frequently associated with the gastrointestinal system and nervous system, consistent with the cholinomimetic actions of rivastigmine. The number of healthy subjects experiencing gastrointestinal-related adverse events (nausea, vomiting) was lower with the patch (6 subjects, 20%) than with the oral treatment (10 subjects, 33%). The numbers of subjects experiencing nervous system-related adverse events (headache, dizziness, insomnia) were 8 (27%) with the patch and 10 (33%) with the oral treatment.
DISCUSSION
A novel rivastigmine patch has been developed and offers the first transdermal treatment for the treatment of AD. The PK profile of rivastigmine has been described extensively following intravenous (IV) and oral administrations.15,20-29 This is the first study to compare the relative bioavailability of rivastigmine from the patch with a reference oral solution. Elderly volunteers were recruited for the study to better represent the target population. The rivastigmine patch demonstrated a smoother rivastigmine concentration-time profile with markedly less fluctuation between maximum and minimum plasma concentrations, compared with the oral solution. Systemic exposure (AUC) after the 9.5 mg/24-h patch was approximately 5 times higher than that after the dose of 3 mg oral solution, while Cmax with the patch was 20% lower than after the oral solution. These findings are consistent with another study comparing the rivastigmine patch with oral capsules in AD patients.30 The rivastigmine patch provides the PK profile it was developed to achieve.
Rivastigmine is metabolized by its target enzymes AChE and BuChE to its major metabolite NAP226-90. Metabolism of rivastigmine does not involve the cytochrome P450 system. NAP226-90 is pharmacologically inactive, but it is an indicator of the extent of rivastigmine metabolism, in particular of the difference in the extent of the first-pass effect between oral and transdermal administration. As assessed by the metabolite-to-parent AUC ratio, which was markedly lower with patch administration (0.67 ± 0.19) than with oral dosing (3.49 ± 3.44), less NAP226-90 was formed following patch application, presumably because of the lack of presystemic (first-pass) metabolism. This is consistent with historic observations after rivastigmine IV administration, in which the metabolite-to-parent AUC ratio was reported to be 0.53 ± 0.15,26 thus suggesting that similar metabolism occurs after transdermal and IV rivastigmine administrations.
Consistent with historic data, adverse events were most frequently associated with the nervous and gastrointestinal systems. However, the frequency of gastrointestinal-related adverse events was substantially lower with the patch than with the oral solution, even though the rivastigmine plasma exposure (AUC) was more than 5 times higher with the transdermal patch. The slow rise in plasma concentrations, and sustained plateau concentration observed in the PK profile of the 9.5 mg/24-h (10 cm2) patch is believed to contribute to diminishing the occurrence of cholinergic adverse events that have been attributed to the sudden rise in rivastigmine plasma concentration resulting from oral administration.16
Differences in the total occurrence and distribution of adverse events between the 2 treatments suggest a superior tolerability profile with the 9.5 mg/24-h (10 cm2) rivastigmine patch compared with oral rivastigmine, which has been confirmed in a large clinical trial in AD patients.31 At the same time, comparable exposure of the 9.5 mg/24-h rivastigmine patch to the maximum recommended 12 mg/day oral dose30 supports data from a large clinical trial in which the 9.5 mg/24-h rivastigmine patch provided similar efficacy to highest prescribed doses of capsules.31
The rivastigmine patch has the potential to provide dual inhibition of AChE and BuChE smoothly and steadily for 24 h. By providing smooth and continuous delivery of rivastigmine into the blood-stream, patch administration may provide sustained efficacy with reduced side effects, potentially improving patient compliance and continued benefits. In clinical practice, patients are recommended to take oral rivastigmine with a full meal to slow tmax. Patients and caregivers using the patch will no longer need to center their medication management around meal times. Additional advantages include the convenience of once daily dosing, easy access to an optimal therapeutic dose (in clinical practice de novo patients will start on a 4.6 mg/24-h [5 cm2; 9 mg dose load] patch before increasing to the 9.5 mg/24-h [10 cm2; 18 mg dose load] patch), and visual reassurance that the medication is being taken. A large clinical trial has already demonstrated that caregivers of AD patients prefer the rivastigmine patch to oral treatment.32
CONCLUSION
The 9.5 mg/24-h rivastigmine patch delivered, on average, approximately 45% of the loaded dose of 18 mg when applied to the upper back of healthy elderly subjects. Rivastigmine plasma exposure (AUC) following patch application was approximately 5 times higher than that provided by a 3 mg oral dose, while Cmax was 20% lower than following the oral dose. Relative bioavailability was approximately 250% based on dose per kg body weight-normalized AUC. Despite much higher exposure (reported to result in greater efficacy), gastrointestinal tolerability appears to be more favorable following patch administration, compared with oral rivastigmine. Patch administration may prove to be an efficient way to treat AD with rivastigmine.
ACKNOWLEDGEMENTS
The authors are grateful to Dr Frank Theobald from LTS Lohmann Therapie-Systeme AG, Andernach, Germany, for analyzing the rivastigmine residues in worn patches.
Financial disclosure: This study was sponsored by Novartis Pharma AG, Basel, Switzerland. MDS Pharma Services received a grant from Novartis to cover the costs of this study. GL, FP, GS, HAH, BK, YYH, and SAD are employees of Novartis.
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