ABSTRACT:The dopamine agonist rotigotine was developed for the treatment of Parkinson's disease and restless legs syndrome. Disposition, metabolism, elimination, and absolute bioavailability of rotigotine were determined in six healthy male subjects by using two different forms of administration in a randomized sequence with a crossover design.

The absorption, distribution, metabolism and elimination of the anti-epileptic drug lacosamide were determined in 10 healthy male volunteers following intravenous or oral administration in a single-center, open-label, single-dose trial. Volunteers were randomized to receive either a continuous intravenous infusion of 100 mg (40 μCi) [¹⁴C]-lacosamide administered over 60 min, or a 100 mg (40 μCi) [¹⁴C]-lacosamide dose given as an oral solution. During the infusion, total radioactivity concentrations reached peak levels at 1 h post dose followed by a decline of 71 % within 24 h. More than 97 % of radioactivity was excreted within 168 h; 96.8 % in urine and 0.3 % in feces. Following oral administration, total radioactivity concentrations increased to peak levels within 0.5 h followed by a decline of 65 % within 24 h. Approximately 94.6 % of radioactivity was excreted within 168 h after oral administration, 94.2 % by the kidneys and 0.4% in feces. A comparison of AUC values (po/iv) of unchanged lacosamide indicates a high absolute bioavailability. The metabolic profile was analyzed using pooled urine samples, and following intravenous and oral administration, respectively, a total of 38 and 34 % unchanged lacosamide, 28 and 28 % of the desmethyl metabolite and 19 and 17 % of a polar fraction were measured. Additional metabolites were identified only in small amounts (<3 %). In plasma at maximum concentration, most of the total radioactivity was found as unchanged drug after intravenous and oral dose. The plasma concentration curves of total radioactivity following intravenous and oral administration were similar.

Background/Aims: To evaluate the bioequivalence of intravenous and oral lacosamide (tablet), an antiepileptic drug. Methods: Two randomized, single-dose (200 mg) trials were conducted: a 2-way trial (study A, 15-min infusion, oral tablet) and a 3-way crossover trial (study B, 30- and 60-min infusions, oral tablet). Twenty four healthy men participated in study A and 27 in study B. Eighteen blood samples were taken before to 72 h after lacosamide administration during each treatment period, followed by a 1-week washout. Safety and the ratio of intravenous/oral lacosamide for AUC_0–tz (area under the concentration-time curve from zero up to the last measurable plasma concentration) and C_max (maximum plasma concentration) were evaluated. Results: For AUC_0–tz and C_max, 90% confidence intervals for the ratio of intravenous/oral lacosamide fell within the predetermined bioequivalence range (80–125%) for 30- and 60-min infusions. In study A, all adverse events (AEs) were mild, with no discontinuations. In study B, 3 volunteers discontinued due to AEs; one serious AE (epiglottitis) was reported. No clinically relevant effects on vital signs, electrocardiograms or laboratory parameters and no AEs relating to infusion site were reported. Conclusion: Intravenous infusions (15, 30 and 60 min) of 200 mg lacosamide are as well tolerated as the oral tablet. Bioequivalence was demonstrated for 30- and 60-min infusions; therefore, direct conversion from oral to intravenous lacosamide, or vice versa, is possible.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Rotigotine transdermal patch is a new non-ergolinic dopamine agonist developed for the treatment of Parkinson's disease and restless legs syndrome.• Peripheral dopaminergic side-effects of dopamine agonists such as nausea and vomiting can be prevented by the antiemetic agent domperidone. WHAT THIS STUDY ADDS• The study results show no evidence for an interaction of domperidone on bioavailability and steady-state pharmacokinetics of transdermal rotigotine.• Co-administration of domperidone and rotigotine does not require dose adjustments for rotigotine transdermal patch. AIMSTo evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODSSixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h), 10 cm 2 , total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTSThe primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0-24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0-24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0-tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONSNo changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone.

In nonclinical drug development targeting the central nervous system (CNS), the quantitative determination of extracellular brain concentrations of neurotransmitters is a key challenge. In some CNS disorders, the monitoring of the modified profile of neurotransmitter release such as that of histamine may explain the mechanism of action of the drug candidate. Microdialysis is a commonly used method for sampling extracellular levels of neurotransmitters/drug candidates in small laboratory animals. Detection and quantification of extracellular levels of neurotransmitters remain an analytical and technical challenge owing to the low concentrations of neurotransmitters collected, the small microdialysis sample size, and the high amount of inorganic salts. A precolumn derivatization strategy prior to hydrophilic interaction liquid chromatography (HILIC)-tandem mass spectrometry analysis is proposed to quantify histamine release after administration of a CNS research compound. Derivatization using propionic anhydride dissolved in organic solvent combined with the HILIC approach effectively eliminated three time-consuming steps, organic layer transfer, dry down, and reconstitution, all of which are required by traditional reversed-phase liquid chromatography. The formation of propionylated amides, performed under mild conditions, required no further sample cleanup. After a dual microdialysis probe implantation into the prefrontal cortex (neurotransmitters) and in the inferior vena cava of rat (drug candidate), microdialysate fractions were collected every 15 min for 8 h and stored frozen at -20 °C until analysis. The method was validated using 10 μL microdialysate, achieving low limits of quantitation of 83.4 and 84.5 pg.mL(-1) for histamine and 1-methylhistamine, respectively. These limits were suitable to assess kinetic release of neurotransmitters and are compatible with those obtained by microdialysis sampling. This method provided the required selectivity, sensitivity, accuracy, and precision to assess release kinetics of histamine and 1-methylhistamine in several hundred rat brain microdialysates after intravenous infusion of CNS drug candidates.