On the Stereoselective Pharmacokinetics of Eflornithine and Prediction of Drug Tissue to Plasma Concentration Ratios

Abstract: Eflornithine is one of two registered drugs for the treatment of late-stage human African trypanosomiasis, a uniformly fatal neglected disease with sixty million people are at risk of being infected. Eflornithine is efficacious but the cumbersome intravenous administration leaves numerous patients untreated. A simplified mode of administration, preferably oral, would enable more patients having access to treatment. The trypanostatic agent eflornithine is administered as a racemate where the L – form has a several-fold greater in vitro potency compared to the D – enantiomer. Despite the difference in potency of the enantiomers, the stereoselective pharmacokinetics of eflornithine has not been considered. This thesis aimed to study L – and D – eflornithine pharmacokinetics in the rat, in Caco-2 cells and in late-stage human African Trypanosomiasis patients. A secondary aim was also to develop a general method for predicting drug tissue to plasma concentration ratios. In the rat, eflornithine displayed stereoselective absorption where the more potent L – form had an approximately 50% lower fraction absorbed compared to D – eflornithine. The stereoselective mechanism was not detected in the present Caco-2 cell assay. Late-stage HAT patients, treated with racemic oral eflornithine, had an approximate 50% lower exposure of L – compared to D – eflornithine, similar to those in rat. The findings suggested that previous attempts to develop an oral eflornithine dosage regimen have failed due to unfavorable stereoselective absorption. High plasma exposure for both L – and D – eflornithine were significantly correlated to the probability of being cured. For the secondary aim of this thesis, the novel method to predict drug tissue distribution, based on a measured volume of distribution in combination with drug lipophilicity performed reasonably well. Predicted drug tissue to plasma concentration ratios agreed reasonably well with experimentally determined values with 85% being within a factor of ±3 to experimental values (n=148). In conclusion, this thesis present the stereoselective pharmacokinetics of eflornithine that can give information on whether a much needed oral eflornithine can be developed or not. In addition, the thesis also presents a general method to predict drug tissue to plasma concentration ratios.