This study aimed to characterize the stereoselective pharmacokinetics of oral
eflornithine in 25 patients with late-stage Trypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations of L- and D-
eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of the T. brucei gambiense parasites. Patients were randomly allocated to receive either 100 (group I, n=12) or 125 (group II, n=13) mg/kg of
body weight of
drug every 6 h for 14 days. The concentrations of L- and D-
eflornithine in the plasma and CSF samples were measured using a stereospecific liquid chromatographic method. Nonlinear mixed-effects modeling was used to characterize the plasma pharmacokinetics. The plasma concentrations of L-
eflornithine were on average 52% (95% confidence interval [CI], 51, 54%; n=321) of the D-enantiomer concentrations. The typical oral clearances of L- and D-
eflornithine were 17.4 (95% CI, 15.5, 19.3) and 8.23 (95% CI, 7.36, 9.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of
eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma
drug exposure, although it was not more pronounced for the L-enantiomer than for that of total
eflornithine. This study may explain why oral treatment for late-stage human
African trypanosomiasis (HAT) patients with racemic
eflornithine has previously failed; the more potent L-enantiomer is present at much lower concentrations in both plasma and CSF than those of the D-enantiomer.
Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further.