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This study aimed to characterize the stereoselective pharmacokinetics of oral eflornithine in 25 patients with late-stageTrypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations ofl - andd -eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of theT. 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 ofl - andd -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 ofl -eflornithine were on average 52% (95% confidence interval [CI], 51, 54%;n = 321) of thed -enantiomer concentrations. The typical oral clearances ofl - andd -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 thel -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 potentl -enantiomer is present at much lower concentrations in both plasma and CSF than those of thed -enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further.

antimicrobial agents and chemotherapy

Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness