Research Areas and Methods
Our first aim was to select a suitable candidate serving as water soluble pro-drug of Levodopa (LD) for subcutaneous infusions to treat Parkinson´s disease. Small and short-term clinical pharmacokinetic studies were used for development steps. One candidate (Glycerol-levodopa) showed a reduced absolute bioavailability and was postponed in favor of Penta-Dopa, our development candidate. Then we studied the influence of oral doses and dose distributions of two decarboxylase inhibitors (DC-I), i.e. benserazide and carbidopa on LD plasma levels. The observation of a sudden effect of oral DC-I on LD levels and the interactions with the catechol-O-methyl-transferase (COMT) inhibitor Opicapone® drew our attention to a new treatment principle of thorough inhibition of peripheral levodopa degradation.
This innovative application principle (BRM-203) (working title) triples plasma levels and half-life of LD and thereby reduces the LD drug dose needed per day significantly compared to other LD infusion therapies, such as AbbVie’s recently launched Produodopa® or Tanabe’s ND0612. As shown in our phase I studies, the new principle works favourably in combination with any soluble LD source, such as Levodopa/Arginine, Foslevodopa, and our own prodrug Pentadopa.
Due to the impressive increase of the reachable LD plasma concentration, made possible by the BRM-203 principle, small and patient-friendly patch pumps can be used as a new sc delivery mode in PD therapy, that are easy-to-use and offer exceptional benefit. For instance, a patch pump volume of only 2 ml applied over 24 h, including generally recommended night-time dose reduction of 50 %, is enough to generate steady state LD plasma levels of 2.200 – 2.500 ng/ml. With the exception of relatively few patients in very severe condition, this allows to treat most advanced PD patients of different severity grades adequately, with good skin tolerance. If needed in individual cases, oral add-on of 3 × 50-100 mg LD can be provided, whereby the extremely prolonged half-life of around 5 hours prevents any clinically relevant fluctuations of the LD plasma concentration.