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

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

  • Antimicrob Agents Chemother. 2015 Feb;59(2):1299-307. doi: 10.1128/AAC.04101-14.
R Jansson-Löfmark 1 K Na-Bangchang 2 S Björkman 3 F Doua 4 M Ashton 5
Affiliations

Affiliations

  • 1 Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden CVMD iMed DMPK, AstraZeneca R&D, Mölndal, Sweden rasmus.jansson.lofmark@astrazeneca.com kesaratmu@yahoo.com.
  • 2 Thammasat University, Faculty of Allied Health Sciences, Krung Thep Maha Nakhon, Thailand rasmus.jansson.lofmark@astrazeneca.com kesaratmu@yahoo.com.
  • 3 Uppsala University, Department of Pharmaceutical Biosciences, Uppsala, Sweden.
  • 4 Project de Recherches Cliniques sue la Trypanosomiasie PRCT, B.P. Daloa, Cote d'Ivoire.
  • 5 Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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.

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