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Enantiospecific Rea...
Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness
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- Jansson Löfmark, Rasmus, 1979 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
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Na-Bangchang, K. (author)
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Bjorkman, S. (author)
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Doua, F. (author)
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- Ashton, Michael, 1955 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
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(creator_code:org_t)
- American Society for Microbiology, 2015
- 2015
- English.
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 59:2, s. 1299-1307
- Related links:
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https://aac.asm.org/...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- HUMAN AFRICAN TRYPANOSOMIASIS
- CEREBROSPINAL-FLUID
- ALPHA-DIFLUOROMETHYLORNITHINE
- ORNITHINE-DECARBOXYLASE
- COMBINATION
- THERAPY
- DRUG ABSORPTION
- MODEL
- MELARSOPROL
- ENANTIOMERS
- PLASMA
- Microbiology
- Pharmacology & Pharmacy
Publication and Content Type
- ref (subject category)
- art (subject category)
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