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Enantiospecific reassessment of the pharmacokinetics and pharmacodynamics of oral eflornithine against late-stage Trypanosoma brucei gambiense sleeping sickness.

Abstract
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.
AuthorsR Jansson-Löfmark, K Na-Bangchang, S Björkman, F Doua, M Ashton
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 2 Pg. 1299-307 (Feb 2015) ISSN: 1098-6596 [Electronic] United States
PMID25512417 (Publication Type: Journal Article, Randomized Controlled Trial)
CopyrightCopyright © 2015, American Society for Microbiology. All Rights Reserved.
Chemical References
  • Trypanocidal Agents
  • Eflornithine
Topics
  • Administration, Oral
  • Adolescent
  • Adult
  • Eflornithine (pharmacokinetics, pharmacology, therapeutic use)
  • Female
  • Humans
  • Male
  • Middle Aged
  • Stereoisomerism
  • Trypanocidal Agents (pharmacokinetics, pharmacology, therapeutic use)
  • Trypanosoma brucei gambiense (drug effects)
  • Trypanosomiasis, African (drug therapy, metabolism)
  • Young Adult

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