Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Background & Aim: Malaria-endemic areas present increasing symptoms of resistance to the current first line treatments, compromising artemisinin combination therapies. Therefore, new compounds with a different mechanism of action must be developed for use in combination with existing therapies to combat resistance. New compounds that undergo redox cycling have been identified, which amplifies oxidative stress levels within the erythrocyte and generates ROS when oxidised back to the original molecule. In part of a PhD project and larger MRC Ship project, the aim of this study was to investigate in vitro ADME, as well as in vivo pharmacokinetics of novel antimalarial compounds and assess candidates in new combinations.
Methods: In vitro ADME experiments are first conducted to predict physiological characteristics of compounds. Favourable in vitro activity and ADME profiles encourages further examination in an in vivo mouse model. Mice are administered orally and intravenously with compounds at 20 mg/kg and 5 mg/kg, respectively to determine pharmacokinetic parameters. Strong in vitro activity and good in vivo exposure are two main factors determining the compound's fate to progress as viable combination candidates with existing antimalarials (artemisone) and novel artemisinin-like compounds.
Results: The promising in vitro activity (IC50: 15nM in NF54) and ADME results obtained prompted further in vivo pharmacokinetic investigation of one compound in particular, namely PhX6, which is a derivative of Methylene blue. It presented a good bioavalability (>60%) and long half-life (8hrs) when tested in mice. This compound, among other promising compounds, will be combined with artemisone, as well as novel non-DHA forming artemisinin derivatives to investigate their interaction.
Conclusions: Optimal pharmacokinetic parameters are critical to achieve significant efficacy levels for in vivo parasite suppression. Therefore we selected the compounds that presented the most desirable ADME and pharmacokinetic parameters to be investigated in novel combinations. These compounds are very similar to methylene blue and literature suggests that they will have a synergistic interaction when combined with an artemisinin, as this was found to be true for methylene blue and artemisinin combinations. Compounds presenting synergy will finally be tested in a SCID mouse model to test efficacies against the true parasite target.
