title: 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.
authors.affiliation: 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.
authors.forename: R
authors.identifier: http://orcid.org/0000-0003-1773-197X
authors.initials: R
authors.lastname: Jansson-Löfmark
authors.affiliation: Thammasat University, Faculty of Allied Health Sciences, Krung Thep Maha Nakhon, Thailand rasmus.jansson.lofmark@astrazeneca.com kesaratmu@yahoo.com.
authors.forename: K
authors.initials: K
authors.lastname: Na-Bangchang
authors.affiliation: Uppsala University, Department of Pharmaceutical Biosciences, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Björkman
authors.affiliation: Project de Recherches Cliniques sue la Trypanosomiasie PRCT, B.P. Daloa, Cote d'Ivoire.
authors.forename: F
authors.initials: F
authors.lastname: Doua
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000518:Eflornithine / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism; D014344:Trypanocidal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D014347:Trypanosoma brucei gambiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014344:Trypanocidal Agents; D000518:Eflornithine