Synthesis of Carbazole Derivative PLX01107 and its Pharmacokinetics for Various Administration Routes in CD-1 Mice

Abstract

The substituted carbazole drug PLX01107 is being developed for the treatment of invasive pulmonary aspergillosis. A synthetic method for PLX01107 drug substance was developed in order to produce the required amount of drug substance of a quality suitable to support preclinical trials. An analytical method using HPLC-MS/MS was employed to determine the drug concentration in whole blood and internal organs. Preclinical trials of the new drug found that PLX01107 possessed linear pharmacokinetics in the i.v. dose range 5 – 20 mg/kg in CD-1 mice. Pharmacokinetic modeling determined the optimum i.v. dose regime for attaining the maximum effective concentration as a loading dose of 5 mg/kg with a maintenance dose of 5 mg/kg every 12 h. Analysis of the PLX01107 content in various organs found that lungs of test animals had the maximum concentrations after both i.v. and oral administration. This gave the developed drug a considerable advantage with respect to targeted delivery of the active ingredient.