Jan-Peer Elshoff

Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies.

BACKGROUND The dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinsons disease (PD) and restless legs syndrome. OBJECTIVE This article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. METHODS One Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm(2) patch versus 2 × 20 cm(2) patches (SP651) and from a 15 cm(2) patch versus 1 × 5 cm(2) + 1 × 10 cm(2) patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. RESULTS Release of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). CONCLUSIONS Continuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area.

Comparison of the bioavailability and adhesiveness of different rotigotine transdermal patch formulations

Abstract Objective: Rotigotine transdermal patch is approved for the treatment of early and advanced idiopathic Parkinson’s disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS). A cold chain manufacturing and distribution process was temporarily implemented in 2008, as this reduced the crystal formation reported within patches stored at room temperature. In order to overcome the crystallization issue and meet EMA and FDA requirements, a new room temperature stable formulation was developed. The three studies reported here were conducted to determine whether the new room temperature stable patch demonstrated similar bioavailability and adhesiveness to the original and intermediate patches. Methods: Data are reported from three cross-over studies that compared the original, cold chain and room temperature stable patch. Two open-label bioequivalence studies investigated the 2 mg/24 h dosage in healthy individuals (SP951, n = 52 [Clinicaltrials.gov: NCT00881894]; SP0987, n = 50 [NCT01059903]) and a double-blind patch adhesiveness study investigated the 8 mg/24 h dosage in patients with PD (SP1066, n = 56 [NCT01338896]). Results: Plasma concentration–time curves and geometric means for pharmacokinetic parameters were similar for the cold chain vs. original patch in SP951 (AUC(0–tz): 2.68 vs. 2.71 ng/mL*h; point estimate: 0.99 [90% confidence interval (CI): 0.91, 1.07]) (Cmax: 0.131 vs. 0.136 ng/mL; 0.96 [0.89, 1.04]) and for the room temperature stable vs. cold chain patch in SP0987 (AUC(0–tz): 4.51 vs. 4.87 ng/mL*h; 0.90 [0.84, 0.97]) (Cmax: 0.23 vs. 0.23 ng/mL; 0.95 [0.88, 1.02]). In both studies, 90% CIs for ratios of AUC(0–tz) and Cmax were within the bioequivalence acceptance range (0.8–1.25). In SP1066, overall median adhesiveness scores were similar for cold chain (0.5 [range: 0–4]) and room temperature stable (0 [0–4]) formulations. Conclusion: These results demonstrated bioequivalence and indicated similar adhesiveness of the approved room temperature stable rotigotine patch with the original and cold chain patches. Potential limitations include the enrolment of healthy volunteers in the bioequivalence studies, as these individuals were likely to be younger than the general PD or RLS population.

Influence of transdermal rotigotine on ovulation suppression by a combined oral contraceptive

AIMS To assess the influence of the transdermally applied dopamine agonist rotigotine on ovulation suppression by a combined oral contraceptive (0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel) in a randomized, double-blind crossover study in 40 healthy females. METHODS Treatment A consisted of the combined oral contraceptive for 28 days plus rotigotine for the first 13 days (2 mg (24 h)(-1) on days 1-3, 3 mg (24 h)(-1) maintenance dose thereafter). During treatment B, subjects received matching placebo patches instead of rotigotine. Pharmacodynamic parameters (progesterone, oestradiol, luteinizing hormone, and follicle stimulating hormone serum concentrations), pharmacokinetic parameters for ethinyloestradiol/levonorgestrel and rotigotine, and safety and tolerability of the treatment were assessed. RESULTS Progesterone serum concentrations remained below 2 ng ml(-1) in all subjects during the luteal phase. Median serum concentrations of all other pharmacodynamic parameters were similar during both treatments. Pharmacokinetic parameters C(max,ss) and AUC(0,24 h)(ss) at steady state were similar with or without co-administration of rotigotine for both ethinyloestradiol and levonorgestrel with geometric mean ratios close to 1 and 90% confidence intervals within the acceptance range of bioequivalence (0.8, 1.25): C(max,ss) 1.05 (0.93, 1.19), AUC(0,24 h)(ss) 1.05 (0.9, 1.22) for ethinyloestradiol; C(max,ss) 1.01 (0.96, 1.06), AUC(0,24 h)(ss) 0.98 (0.95, 1.01) for levonorgestrel. Mean plasma concentrations of unconjugated rotigotine remained stable throughout the patch-on period (day 13). CONCLUSIONS Concomitant administration of 3 mg (24 h)(-1) transdermal rotigotine had no impact on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive containing 0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel, suggesting that the dopamine agonist does not influence contraception efficacy.

Pharmacokinetics of lacosamide in healthy korean male volunteers.

Aim: The aim of this study was to evaluate the pharmacokinetics (PK) of single and repeated doses of lacosamide in healthy male Korean volunteers and to compare the PK profile of lacosamide in Korean and Caucasian populations. Methods: In a double-blind, placebo-controlled, parallel-group, dose-escalation trial, 16 volunteers received a single dose (50 mg) of lacosamide or placebo, and 32 volunteers were administered single/repeated twice-daily doses (100 or 200 mg) of lacosamide or placebo. Results: For multiple doses of 100 and 200 mg twice daily, the geometric means Cmax,ss were 6.23 (15.0) and 13.13 (8.9) µg/ml respectively, and AUCτ,ss values were 52.10 (17.0) and 112.35 (13.0) µg·h/ml, respectively. Values for both parameters were relatively higher than those seen in Caucasians. To further describe ethnic differences, population PK analysis was assessed. A one-compartment model with first-order absorption and elimination was selected and effects of CLcreatinine on CL/F and body surface area on V/F were included in the final model. Conclusion: There were no other ethnic differences in the PK profile of lacosamide between Koreans and Caucasians based on the population PK analysis, except for the demographic differences.

No influence of the CYP2C19‐selective inhibitor omeprazole on the pharmacokinetics of the dopamine receptor agonist rotigotine

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 Cmax,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 Cmax,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.

Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis–Ekbom disease)

OBJECTIVE To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). METHODS This multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (VSS/f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. RESULTS Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and VSS/f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50-1121.51]; 1 mg/24 h: 671.72 [459.11-982.80]; 2 mg/24 h: 937.56 [658.50-1334.89]; 3 mg/24 h: 1088.77 [723.47-1638.53]; VSS/f: 5403.16 [2850.67-10,241.17]; 6220.79 [3842.05-10,072.28]; 7114.01 [4547.88-11,128.07]; 6037.92 [3598.36-10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). CONCLUSIONS Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.

Randomized, double-blind, crossover study of the adhesiveness of two formulations of rotigotine transdermal patch in patients with Parkinson’s disease

Abstract 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 (40 cm2). 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 (mean ± SD 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.