Jan-Peer Elshoff

Objective: Despite introduction of several antiseizure medications over the past two decades, treatment options for childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remain limited. We report the innovative adaptive design of an ongoing phase 2/3 trial to evaluate efficacy, safety, and tolerability of brivaracetam (BRV) monotherapy in patients 2–25 years of age with CAE or JAE.Methods: N01269 (ClinicalTrials.gov: NCT04666610; start: July 2021; expected completion: 2024) is a randomized, dose‐finding and confirmatory, double‐blind, placebo‐controlled, parallel‐group, multicenter trial. The trial consists of a dose‐selection and assessment for futility stage, followed by an optimal‐dose stage after interim analysis. Both stages include an up to 2‐week screening period, a 2‐week placebo‐controlled period, and an 11‐week active treatment period (10 weeks of initial treatment followed by a 24‐hour electroencephalogram [EEG] and an additional week of active treatment for 24‐hour EEG assessment). Patients who are absence seizure‐free will enter an up to 4‐week randomized withdrawal period. Efficacy assessments will be based on 24‐hour EEG and seizure diaries.Significance: This two‐stage adaptive trial design allows investigation of two potentially efficacious BRV doses, where one dose is dropped in favor of the other dose with a better benefit–risk profile. This allows for a combined phase 2 dose‐finding and phase 3 confirmatory efficacy trial, which reduces the number of patients needed to be recruited and reduces trial duration. A randomized withdrawal period is included to evaluate sustainability of treatment effect over time and to allow for placebo control while minimizing placebo exposure. Use of EEG capture in addition to seizure diaries offers a robust mechanism of detecting seizure activity and measuring treatment effect. Positive efficacy and safety/tolerability data may support the use of BRV as monotherapy for CAE or JAE, providing another treatment option and representing long‐delayed progress in the treatment of absence seizures in these populations.

Objective: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15‐min intravenous (IV) infusion and bolus (≤2‐min injection).Methods: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open‐label trial in patients ≥1 month to n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15‐min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug‐related TEAEs (15‐min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred.Significance: IV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15‐min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15‐min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

Objective: In patch-based transdermal drug delivery, adhesiveness is critical for safe and effective treatment, especially in Parkinson's disease (PD) where excessive sweating is common. This study compared the adhesiveness of two transdermal patch formulations of rotigotine (improved room temperature-stable [PR2.3.1/Treatment A] and intermediate cold storage product [PR2.1.1/Treatment B]), using the largest patch size (40cm(2)).Methods: PD0018 (NCT02230904) was a multicenter, randomized, double-blind, crossover study. PD patients received Treatments A and B in randomized order for 2 days each. Patch adhesiveness was measured immediately after patch application and 24 hours thereafter (before removal). Primary variable: change in average investigator-rated adhesiveness score between treatments, per modified European Medicines Agency scale (EMA/CHMP/QWP/911254/2011, 2012).Results: Fifty-seven patients were randomized; 56 patients completed the study. Five patients were excluded from analysis for accidental unblinding. Treatment A had better average adhesiveness score (meanSD Treatment A - Treatment B: 1.115 +/- 1.635). A higher percentage of patients on both days had patch adhesiveness 95% at 24 hours for Treatment A (first day: 65.4%, second day: 71.2%) vs. Treatment B (46.2%, 36.5%), and were satisfied with patch adhesiveness of Treatment A (first day: 75.0%, second day: 73.1%) vs. Treatment B (65.4%, 59.6%). Average patch-wear duration was similar between formulations (23.761 hours vs. 23.495 hours per patch). Both formulations were well tolerated with no new safety observations.Conclusion: Results indicated greater adhesiveness for the improved room temperature-stable formulation (PR2.3.1) vs. intermediate cold storage product (PR2.1.1) using the largest patch-size, with comparable safety and skin tolerability.

This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson’s disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300–600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1–2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration–time curve (AUC) and maximum plasma drug concentration (C _max), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug–drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D₃/D₂/D₁ dopamine receptor agonist in the treatment of PD and RLS.

Rotigotine, a non‐ergolinic dopamine receptor agonist administered transdermally via a patch, is metabolized by several cytochrome P‐450 (CYP450) isoenzymes, including CYP2C19. This open‐label, multiple‐dose study evaluated the effect of omeprazole, a competitive inhibitor of CYP2C19, on the pharmacokinetics of rotigotine and its metabolites under steady‐state conditions in healthy male subjects (of the extensive metabolizer phenotype, CYP2C19). Subjects received rotigotine 2 mg/24 hours on days 1–3, 4 mg/24 hours on days 4–12, and omeprazole 40 mg once daily on days 7–12 immediately after patch application. Blood and urine samples were collected on days 6 and 12 to evaluate rotigotine pharmacokinetic parameters alone and in the presence of omeprazole. Data from 37 subjects were available for pharmacokinetic analysis. Point estimates (90% confidence intervals, CI) for the ratios of AUC_(0–24)SS and C_max,SS of unconjugated rotigotine for the comparison rotigotine + omeprazole:rotigotine alone were close to 1 (0.9853 [0.9024, 1.0757] for AUC_(0–24)SS and 1.0613 [0.9723, 1.1585] for C_max,SS) with 90% CIs within the acceptance range for bioequivalence (0.80, 1.25). Selective inhibition of CYP2C19 by omeprazole did not alter the steady‐state pharmacokinetic profile of rotigotine or its metabolites. Thus, rotigotine dose adjustment is not required in patients receiving omeprazole, or other CYP2C19 inhibitors.