Jens-Otto Andreas

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.

Tolerability, pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma, saliva, and urine: Saliva as a surrogate of pharmacokinetics in the central compartment

Purpose:  To test for bioequivalence of 200 mg lacosamide oral tablet and syrup formulations. Additional objectives were to compare the pharmacokinetic profile of lacosamide in saliva and plasma, and to evaluate its tolerability.

Advances in epilepsy treatment: lacosamide pharmacokinetic profile

Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial‐onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose‐proportional pharmacokinetics, low inter‐ and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug–drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug–drug interactions, make LCM an easy‐to‐use adjunctive treatment for the management of patients with focal epilepsy.

Lack of Pharmacokinetic Interactions Between Transdermal Rotigotine and Oral Levodopa/Carbidopa

This open‐label phase I trial assessed potential pharmacokinetic interactions between oral levodopa/carbidopa and transdermal rotigotine treatment at steady state. Twenty‐four participants with idiopathic restless legs syndrome (12 per group) received levodopa/carbidopa (100 mg/25 mg bid) and rotigotine (initial dose 2 mg/24 h for 3 days, followed by 4 mg/24 h) in a randomized sequence as monotherapy and in combination during hospitalization for 13 days. Primary pharmacokinetic parameters were AUCss and Cmax,ss of levodopa, carbidopa, and rotigotine at steady state. Mean concentration‐time profiles of the 3 agents were similar during monotherapy and combination treatment. The point estimate for the ratio of geometric means (combined vs monotherapy) for AUCss and Cmax,ss for levodopa (0.98 and 1.04), carbidopa (1.03 and 1.06), and unconjugated rotigotine (1.02 and 0.98) was near unity. All 90% confidence intervals were within the acceptance range for bioequivalence (0.8, 1.25). The most frequently documented adverse events were application site reactions (itching and reddening at application site) and headache. Most adverse events were mild to moderate in intensity, but 2 were of severe intensity (headache and extrasystoles); no serious adverse events occurred. The data presented indicate that rotigotine and levodopa/carbidopa can be coadministered without pharmacokinetic interactions between the compounds.

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.

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.