Comparative Bioavailability Study of a Novel Multi-Day Patch Formulation of Rivastigmine (Twice Weekly) with Exelon® Transdermal Patch (Daily)- A Randomized Clinical Trial.

BACKGROUND: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer's dementia, is administered once daily transdermal patches, enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation was developed with greater convenience for patients' therapeutic management. OBJECTIVE: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once-daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h. DESIGN: Single-center, open-label, randomized, multiple-dose study in healthy male adults in a 2- period, 2-sequence-crossover design with multiple applications. METHODS: Patches were applied on 11 consecutive days for Exelon® and a 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated. RESULTS: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00-125.00%. They were 113.64% (107.33-120.33), 105.14% (98.38- 112.38) and 107.82% (97.78-118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®. CONCLUSION: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once daily in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimer's disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg/24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated. METHODS: This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n = 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg/24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches. RESULTS: Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state [AUC0-τ,ss] (97.4; 88.8-106.9), maximum plasma concentration within the dosing interval τ (profile day) at steady state [Cmax,ss] (99.6; 90.4-109.7) and trough plasma concentration at the end of the dosing interval τ (profile day) at steady state [Cτ,ss] (96.8; 86.2-108.9), demonstrated that both patches were bioequivalent. Evaluation of patch adhesion showed better skin adherence for RIV-TDS as well as dermal response scores (skin tolerability after removal). CONCLUSIONS: For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance. The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28.

Accidental injuries in patients with generalized tonic-clonic seizures. A multicenter, observational, cross-sectional study (QUIN-GTC study).

PURPOSE: Patients with epilepsy have a higher risk of accidental injuries. The aim of this study was to determine the incidence of accidental injuries and quality of life in patients with epilepsy and generalized tonic-clonic seizures and their association with patient-related factors. METHODS: This is an observational, cross-sectional, multicenter study of patients with epilepsy and primary generalized tonic-clonic seizures and/or focal to bilateral tonic-clonic seizures in the routine clinical practice of epilepsy clinics. In a single visit, demographic and clinical data and information on the type and severity of injuries were collected, and patients' quality of life was evaluated with the QOLIE-10 questionnaire. RESULTS: In total, 406 patients with a median age of 41.1 years (range: 13-87) were included; 47.5% were women. Age at onset of tonic-clonic seizures was 25.4 (range: 0-83) years. Epileptic seizures were primary tonic-clonic (67.2%), focal to bilateral tonic-clonic (32.8%), focal with impairment of awareness (23.6%), focal without impairment of awareness (13.5%), absences (14.8%), and myoclonic (9.6%). Etiology was symptomatic or with unknown etiology focal (42.9%), genetic generalized (36.9%), symptomatic or with unknown etiology generalized (18.0%), and others (2.2%). The number of generalized tonic-clonic seizures in the last 12 months was as follows: 1 (41.9%), 2-5 (42.4%), and >5 (15.8%). Antiepileptic treatment at the time of the visit was monotherapy in 44.1% of the patients. The most commonly used drugs were levetiracetam (45.1%), valproate (20.7%), lamotrigine (20.0%), and perampanel (18.7%). In total, 59.6% of the patients had experienced at least one accidental injury associated with tonic-clonic seizures in the last 12 months, the most common being head injuries (35.5%), dental injuries (4.9%), burns (4.9%), and fractures (3.9%). A total of 25.1% had suffered at least one serious injury. The multiple logistic regression model showed that the factors associated with suffering an injury were the following: etiology (symptomatic or with unknown etiology focal and genetic generalized vs. symptomatic or with unknown etiology generalized, p = 0.0008 and p = 0.0077, respectively), number of seizures in the last year (2-5 vs. 1, p = 0.0115; >5 vs. 1, p = 0.0004), and psychiatric comorbidities (p = 0.0151). Patients with injuries had a worse quality of life than patients without injuries, according to the overall QOLIE-10 score (p = 0.0003). CONCLUSIONS: More than half of the patients had accidental injuries related with seizures. Symptomatic or with unknown etiology focal epilepsy and genetic generalized epilepsy, >1 seizure in the last year, and concomitant psychiatric disease are the risk factors associated with accidental injuries in patients with tonic-clonic seizures, with the consequent worsening of quality of life.