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Pharmacokinetics of a Rivastigmine Transdermal Patch Formulation in Healthy Volunteers: Relative Effects of Body Site Application

Gilbert Lefèvre, PhD, Greg Sdek, MD, PhD, Hsun-Lun Aaron Huang, PharmD, Marc Saltzman, MD, Mitchell Rosenberg, MD, Beate Kiese, MSc and Peter Fordham, PhD

From Novartis Pharma AG, Basel, Switzerland (Dr Lefèvre, Ms Kiese); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Sdek, Dr Huang); Parkway Research Center, North Miami Beach, Florida (Dr Saltzman, Dr Rosenberg); and SGS Cephac Europe, Saint Benoit, France (Dr Fordham).

Address for reprints: Dr Gilbert Lefèvre, Novartis Pharma AG, Exploratory Development, WSJ-210.4.25, CH-4002 Basel, Switzerland; e-mail: gilbert.lefevre{at}novartis.com.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
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-cm² 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.

Key Words: Adhesiveness • Alzheimer's disease • pharmacokinetics • rivastigmine • transdermal patch

Slower dose escalation can reduce adverse events observed with rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE),^3,4 as can measures that prolong t_max and reduce C_max.^3,5 Therefore, a transdermal delivery system has been developed for rivastigmine to prolong t_max, achieve a more gradual increase in C_max, and avoid the rapid rise and fall of drug concentration. Transdermal drug administration using a patch formulation is increasingly widely used in many areas of medicine and offers many potential advantages over oral formulations. These include sustained plasma levels, longer duration of action, reduced side effects, and improved compliance due to improved convenience to the caregiver and patient with less frequent dosing. Transdermal systems are also useful for patients with dysphagia and other swallowing difficulties who are unable to take oral medications.

In early clinical studies with the rivastigmine patch, the upper back was used as the standard application site. Additional easily accessed application sites may enhance patient compliance without diminishing rivastigmine exposure. The objectives of the current study were (1) to evaluate the adhesiveness of the rivastigmine transdermal patch at additional body sites (chest, abdomen, thigh, and upper arm), (2) to evaluate how different patch application sites may affect relative bioavailability in healthy subjects, (3) to investigate how patch adhesiveness at different body sites may influence pharmacokinetic parameters, (4) to investigate the potential for skin irritation induced by the patch at different body sites, and (5) to evaluate the systemic tolerability of the patch during the test period.

	METHODS

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Subject Selection and Study Design
This was a single-center, single-dose, open-label, randomized-sequence, crossover, topical application study in 40 healthy men or women aged between 40 and 80 years. Eligible subjects in good general health, as determined by past medical history, physical examination, routine urinalysis, and laboratory and electrocardiogram (ECG) tests performed during a 21-day screening period, were enrolled in the study. Major exclusion criteria included a known hypersensitivity to rivastigmine or similar drugs, dermatological diseases that might interfere with the evaluation of skin irritation at different application sites, excess hair on the application sites, smoking (use of tobacco products in the past 3 months), and a confirmed positive test for hepatitis B or C or HIV. Subjects diagnosed with type 2 diabetes (not requiring insulin), hypertension, or those taking hormone replacement therapy were considered for inclusion in the study, as long as they were stabilized on medication for at least 2 months without change in treatment regimen and had not exhibited any signs of disease progression. The use of concomitant medications, other than those required for type 2 diabetes, hypertension, and hormone replacement, was not allowed during the study. The use of any topical solutions such as (but not limited to) body lotions, sunscreens, or exfoliating washes was also prohibited, and subjects were asked to refrain from strenuous physical exercise from 7 days before dosing until after the study completion evaluation.

A 10-cm² patch, containing 18 mg of rivastigmine, was applied to the skin of 5 selected body locations for 24 hours: upper back, chest, thigh, abdomen, and upper arm. Patch application sites were defined as follows:

• Upper back—above or over the upper part of scapula
  
• Chest—2 to 3 inches below the clavicle and lateral to the sternum
  
• Abdomen—lower abdominal quadrant
  
• Thigh—outer lateral surface
  
• Upper arm—over the deltoid muscle
  

Both left and right sides of the body were used. Each subject experienced a total of five 24-hour patch applications, in 1 of 5 randomly allocated study sequences (Table I). There were 8 subjects per study sequence. Administrations to each of the 5 body sites were separated by a 72-hour washout period. The total domiciled treatment duration, including washouts, was 15 days. Study subjects stayed at the study center for 16 nights (from days –1 to +16). All applications of the rivastigmine patch occurred in the morning before breakfast. For each of the 5 applications (1 for each body site), subjects underwent pharmacokinetic, patch adhesiveness, and skin irritation assessments. Systemic adverse effects were monitored throughout the study.

Safety assessments included physical examinations, ECGs, vital signs, standard clinical laboratory evaluations (blood chemistry, urinalysis, hematology), and adverse event monitoring. The study was performed in compliance with the 1996 Harmonized Tripartite Guidelines for Good Clinical Practice; Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community; the US Code of Federal Regulations dealing with clinical studies; and the Amended Declaration of Helsinki. Protocols and all information for participants were reviewed by the Western Institutional Review Board (WIRB, Olympia, Wash). All participants provided written informed consent.

Pharmacokinetics
A 36-hour pharmacokinetic sampling was performed to characterize bioavailability of rivastigmine from patch application at each body location. Blood samples (3 mL) were collected at 0 (predose), 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 22, 24, 26, 28, 32, and 36 hours postapplication. The harvested plasma was 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. Concentrations of rivastigmine and its metabolite, NAP226-90, in plasma were assessed using liquid chromatographic tandem mass spectrometry, according to the methods of Pommier and Frigola.⁶ The limit of quantification (LOQ) was 0.2 ng/mL for both compounds using 0.5 mL of plasma sample. Reproducibility of the method for the determination of rivastigmine was demonstrated prior to sample analysis. Intrarun precision and accuracy were 2.7% and within ±15.0%, respectively, at the LOQ and 4.0% and within ±14.5%, respectively, above the LOQ (for quality control [QC] samples [n = 6] prepared at 0.4, 5, and 25 ng/mL). Pharmacokinetic parameters, C_max, t_max, t, AUC_last, and AUC, were determined using noncompartmental methods (WinNonlin Professional Version 4.0.1, Pharsight Corporation, Mountain View, Calif). Relative bioavailability was assessed using the upper back as the reference site. All worn patches were sent to an independent laboratory for analysis of residual drug content.

Patch Adhesiveness
Both patch adhesiveness (ie, the area of patch attached to the skin 24 hours after patch application) and the residual rivastigmine concentration were determined using the planimetric method. Once the patch was firmly applied by hand at 0 hours, no reapplication or patch recompression was allowed.

Skin Irritation
Each body site was scored for skin irritation before patch administration (0 hours), at the time of patch removal, and 2, 4, 8, 12, and 24 hours after patch removal. Any other reactions possibly linked to skin irritation, such as cracking or peeling, and any undesirable signs, symptoms, or medical conditions occurring after patch application—whether reported spontaneously or upon questioning the subject and whether considered drug related or not—were recorded as adverse events. If deemed useful by the investigator, photographs were taken and kept with the source document. No inferential analysis was performed on safety and tolerability apart from skin irritation data.

Statistical Analyses
It was calculated that a study population of 40 subjects was required to achieve at least 80% power to detect a 15% difference between the reference and test sites for percentage adhesiveness and a 25% difference for bioavailability primary endpoints ( = 0.05, 2-sided).

Log-transformed C_max, AUC_last, AUC, and percent adhered area were analyzed using linear mixed-effects models, with body site, sequence, and period as fixed factors and subject within sequence as a random factor. In the analysis of pharmacokinetic parameters, log-transformed percent adhered area was also included as a covariate. The ratios of geometric means between test body sites and the upper back reference site were calculated to determine bioavailability, along with the corresponding 90% confidence intervals (CIs). The interaction of log-transformed percent adhered area with body site was included in the mixed model to test the relationship between patch adhesiveness performance and pharmacokinetic parameters.

A proportional odds model, with time and body site as fixed factors and subject within sequence as a random factor, was used to study the effects of body site on the skin irritation measured by dermal response grouped into 3 categories: 0 (no erythema), 1 (equivocal erythema), and >1 (erythema). The odds ratio (OR) and 95% CIs were calculated. Drug released was analyzed using a linear effects model. Risk of development of skin erythema at a specific time was assessed as the appropriate OR versus the 24-hour post patch removal data.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Subjects
Forty subjects (17 [42.5%] men) participated in and completed the study. The mean age of the study population was 52.4 ± 9.3 years (range, 40–80 years), mean body weight was 71.7 ± 11.1 kg (range, 50.8–96.5 kg), and mean height was 163.9 ± 8.9 cm (range, 151–182 cm). None of the study subjects were receiving any concomitant medications. With the exception of the results for skin irritation assessments at patch application sites, no systemic adverse events were reported.

Pharmacokinetics
The mean (± SD) plasma concentration-time curves of rivastigmine and its metabolite NAP226-90 are displayed in Figure 1. The pharmacokinetic parameters are summarized in Table II. Rivastigmine was slowly absorbed from all body sites and reached detectable plasma levels after 0.5 to 1.0 hour (Figure 1). Concentrations of rivastigmine reached a plateau at around 8 hours for the upper back and chest, 10 hours for the upper arm, 12 hours for the abdomen, and 16 hours for the outer thigh (Figure 1). Median t_max was 16 hours for all sites except for the thigh, for which it was 22 hours (Table II). The highest exposure levels (AUC and AUC_last) of rivastigmine were obtained when the patch was applied to the upper back, chest, or upper arm (Table II). Data for C_max were also highest for the same 3 body sites (Table II). Elimination t_1/2 of rivastigmine ranged from 3.2 to 3.9 hours. The intersubject variability for the pharmacokinetic parameters determined for rivastigmine was characterized by coefficients of variation of 35% to 47%.

View larger version (25K): [in this window] [in a new window]   Figure 1. Plasma concentration-time profiles of (A) rivastigmine and its metabolite (B) NAP226-90 in healthy subjects following a single 24-hour application of a 10-cm2 rivastigmine patch to different body sites. n = 40; data are mean ± SD.

In general, mean maximum plasma concentrations for NAP226-90 were 2.5 to 3.0 times lower than those of the parent compound. Similar to the rivastigmine profile, AUC and AUC_last of the metabolite NAP226-90 were greatest after patch application to the upper back, chest, or upper arm, with measurable NAP226-90 concentrations appearing in plasma between 2 and 3 hours after patch application for all sites (Figure 1). Plateau concentrations were reached between 12 and 16 hours, except for the thigh body site, for which a plateau was only reached at 22 hours. Median t_max was 16 hours for the upper back and 22 hours for all other body sites. Elimination t_1/2 of NAP226-90 ranged from 4.5 to 5.5 hours. Coefficients of variation for NAP226-90 parameters were 28% to 41%.

Taking the upper back as the reference site, the relative bioavailability of rivastigmine from the other body sites was 100% for the chest, 92% for the upper arm, 80% for the abdomen, and 71% for the thigh. Ratios of geometric means along with 90% CIs versus the upper back site for C_max, AUC_last, and AUC are recorded in Table II. The chest and upper arm sites met the bioequivalence criteria compared with the upper back site, whereas the abdomen and outer thigh sites showed reduced bioavailability.

Patch Adhesiveness and Drug Release
Percentage adhesiveness ranged from 65.9% to 89.3% and was found to be highest when applied to the thigh (89.3% ± 20.1%), followed by the abdomen (83.9% ± 23.9%), upper arm (75.7% ± 25.6%), chest (70.6% ± 27.0%), and upper back (65.9% ± 32.1%). Adhesiveness on the upper back was significantly lower than that on the abdomen (P = .005), thigh (P = .007), and upper arm (P = .049). Nevertheless, only the patch applied to the abdomen body site released a significantly higher drug amount of 7.4 ± 1.6 mg (40.9% ± 9.07% of drug load; P = .005) than 6.5 ± 2.0 mg (36.3% ± 0.8%) released at the upper back, whereas the patches applied to the chest, thigh, and upper arm released 6.5 ± 1.5 mg (36.0% ± 8.3%; P = .855), 6.4 ± 1.3 mg (35.6% ± 6.9%; P = .635), and 6.2 ± 1.2 mg (34.6% ± 6.4%; P = .288) of rivastigmine compared with the upper back, respectively.

With the exception of the chest body site, at which increased adherence was positively correlated with the pharmacokinetic parameters AUC_last (P = .014), AUC (P = .010), and C_max (P = .022), the effect of the percentage of patch adhesiveness on the pharmacokinetic parameters at the other 4 sites was not statistically significant (P > .05 for all parameters at all other sites).

Skin Irritation
At 24 hours, no erythema was observed at the chest or upper arm sites, and only 1 case was reported at each of the abdomen, thigh, and upper back sites. Odds ratio data at earlier assessment times were therefore higher compared with the 24-hour time point, with the risk of developing skin erythema being highest at patch removal (OR: 339.3; CI: 156.6, 735.2) and decreasing with elapsed time: 2 hours (OR: 173.6; CI: 82.2, 366.9), 4 hours (OR: 42.7; CI: 20.9, 87.2), 8 hours (OR: 11.4; CI: 5.6, 23.1), and 12 hours (OR: 3.3; CI: 1.6, 6.9). Calculation of the OR and corresponding 95% CIs revealed that patch application to the abdomen and thigh was more likely to result in the development of skin erythema (OR: 13.7; CI: 8.4, 22.5 and OR: 5.9; CI: 3.7, 9.6, respectively) compared with the upper back reference site, whereas applications to the chest and upper arm were less likely to result in the development of skin erythema (OR: 0.49; CI: 0.3, 0.8 and OR: 0.35; CI: 0.2, 0.6, respectively). No other signs of skin irritation, such as edema and papules, were observed.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Overall, the rivastigmine patch displayed very good adhesiveness. The highest exposures to rivastigmine were obtained when the patch was applied to the upper back, chest, or upper arm. After the initial increase, the rivastigmine patch provided a sustained plasma concentration–time profile over the entire patch application of 24 hours at these sites. The thigh and abdomen sites achieved a relative bioavailability of 80% and 71%, respectively, compared with the upper back. Furthermore, the 90% CIs of the ratio of geometric means for the bioavailability pharmacokinetic parameters (AUCs and C_max) corresponding to the chest and upper arm sites also demonstrated the range required for showing bioequivalence (80%–125%) with the upper back body site. Exposure to the metabolite NAP226-90 was lower but followed the same pattern as for rivastigmine.

Although the abdomen, thigh, and upper arm revealed significantly higher patch adhesiveness than the upper back reference site after 24 hours, the absolute differences in the amounts of drug released remained small. The abdomen was the only body site with significantly more actual drug released than the upper back reference site, yet the difference was only 0.8 mg. Furthermore, although patches applied to the chest, thigh, and upper arm had a higher percentage area attached at 24 hours, the actual amount of drug released was less than for the upper back. It should also be noted that the abdomen, although showing the second best patch adhesiveness performance and the greatest amount of drug released from the patch, achieved the second lowest drug exposure (ie, levels of drug in the plasma). It is possible that this may be due to the quantity of subcutaneous fat absorbing this lipophilic compound, thus diminishing the amount of drug reaching the plasma. However, this remains speculative, and effects of fat "trapping" rivastigmine would necessitate further investigation. Other factors such as age, gender, or body weight might also affect adhesion and skin permeability to transdermal agents. However, any potential effects of study subject characteristics are unlikely to have affected comparative findings between different body sites in the current study because the study was designed to ensure that all subjects received applications to all body parts in 1 of 5 randomly allocated study sequences. Thus, all subjects provided data for all body sites, and it seems reasonable to assume that any potential effects of age, gender, or body weight on adhesion and skin permeability would have applied to all study sequences and all body sites and not affected the conclusions of the current investigation.

Statistical analyses indicated that, with the exception of the chest, there was no significant correlation between percentage of area attached and pharmacokinetic parameters. The 10-cm² patch is in fact quite small (about 3.5 cm in diameter) with limited potential for adhesion variability, and this may have limited the detection of changes in exposure to drug. Nevertheless, variability in patch adhesion was sufficient to detect significant differences between different body sites, so for current purposes, the study design appeared to be appropriate. Thus, within the limits observed in this study, the performance of patch adhesiveness did not appear to be a major factor influencing pharmacokinetic performance.

The 10-cm² patch contains 18 mg of rivastigmine, and about 40% of this dose (ie, approximately 7 mg) was released from the patch over the 24-hour period. This is within the known oral therapeutic dose range of rivastigmine (6–12 mg/d)^7–9 and, as expected, this transdermal dose appeared to produce similar or even higher exposure (AUC) to rivastigmine with lower C_max than oral dosing. Indeed, a 6-mg oral dose was reported to produce an AUC of 71.2 ± 28.2 ng·h/mL and a C_max of 25.6 ± 9.6 mg/mL.¹⁰ In another recently completed study, modeling of steady-state pharmacokinetic data collected in AD patients indicated that a 10-cm² patch produces average drug plasma concentrations similar to those provided by an oral dose of 12 mg/d (Lefèvre et al, data on file). Unlike oral doses, transdermal rivastigmine is not subject to a gastrointestinal and hepatic first-pass effect, which allows a greater systemic bioavailability. This increases the likelihood that a greater quantity of the rivastigmine dose will reach the brain, potentially resulting in greater efficacy. This is supported by the fact that the therapeutic effect is derived predominantly from the parent compound and not the metabolite.¹¹

The 10-cm² rivastigmine patch provides smooth, controlled drug delivery with a C_max that is substantially lower and a t_max that is substantially longer compared with that seen following oral administration, alongside a dramatic reduction in peak-trough fluctuations (Lefèvre et al, data on file). Therefore, although effective doses of the capsule have been associated with relatively high incidences of nausea and vomiting, the pharmacokinetic profile observed in this study might be expected to be consistent with an improved tolerability profile in patients with AD. In this study, the 10-cm² rivastigmine patch was well tolerated by healthy volunteers.

Elimination half-life of rivastigmine (3.2–3.9 hours) was longer than previously reported following oral or intravenous administration (1.4–1.7 hours).^3,10 This difference was probably due to the fact that elimination of rivastigmine following patch application was absorption rate limited, meaning that the elimination rate constant would be higher than the absorption rate (flip-flop). Estimation of t_1/2 could have also been confounded with some diffusion of rivastigmine from the skin (reservoir) into plasma still after patch removal. The same finding was observed for NAP226-90 (4.5–5.5 hours vs 3.2–3.6 hours after patch and intravenous administration, respectively).

Skin erythema was barely visible or mild and self-resolved within 24 hours of patch removal, in line with expectations for a patch applied to the skin for 24 hours. When comparing the likelihood of exhibiting erythema at 24 hours after patch removal, the abdomen and outer thigh body sites showed higher odds ratios of having erythema than the upper back body site, whereas the chest and upper arm body sites showed lower odds.

This rivastigmine patch has the potential to provide dual inhibition of AChE and BuChE smoothly and steadily over 24 hours, which may mean access to optimal doses, permitting greater exposure and improved efficacy. Additional advantages include the convenience of once-daily dosing, simple titration, no requirements for the patient to swallow or take the medication with a full meal, and visual reassurance that the medication has been taken. A large study has recently evaluated the effectiveness of the rivastigmine patch, compared with the capsule and placebo, in approximately 1200 patients with AD. The results of that study will be published separately (in preparation).

In conclusion, the rivastigmine patch displayed very good overall adhesiveness and appeared to provide optimal bioavailability and skin tolerability when worn on the upper back, chest, or upper arm. Thigh and abdomen application sites appeared to provide lower plasma exposure, although these 2 sites showed highest patch adhesiveness. No systemic tolerability problems were reported during the study.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
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. The Parkway Research Center received a grant from Novartis to cover the costs of this study. GL, GS, AH, and BK are employees of Novartis.

DOI: 10.1177/0091270006297748

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Lefèvre, G. Articles by Fordham, P. Search for Related Content PubMed Articles by Lefèvre, G. Articles by Fordham, P. Social Bookmarking                   What's this?