The pharmacokinetics of eflornithine (alpha-difluoromethylornithine) in patients with late-stage T.b. gambiense sleeping sickness.

OBJECTIVE: To investigate the plasma, cerebrospinal fluid (CSF) levels and pharmacokinetics of eflornithine (DFMO) in patients with late-stage T.b. gambiense sleeping sickness who were treated with an oral DFMO at 100 mg/kg or 125 mg/kg body weight every 6 h for 14 days. METHODS: Plasma and CSF concentrations of DFMO were measured during day 10 and day 15 in patients following oral DFMO at 100 mg/kg (group I: n=12) and 125 mg/kg (group II: n=13) body weight every 6 h for 14 days. Clinical and parasitological assessments were performed at 24 h after the last dose of DFMO and at 12 months. RESULTS: Patients in each group had a good initial response, but relapse was observed in six patients (three patients for each group) during 12 months follow-up. Plasma DFMO concentrations did not increase proportionally to doses when the dose increased from 100 mg/kg to 125 mg/kg body weight given every 6 h (60-70% of the expected increase). In most cases, concentration-time profiles of DFMO in each group were best fit using a two-compartment open model with first-order input, with absorption lag-time and first-order elimination. Average trough (C(ss-min)) and average (C(ss-ave)) plasma DFMO concentrations during steady state varied between 189-448 nmol/ml and 234-528 nmol/ml, following 100 mg/kg and 125 mg/kg dose group, respectively. C(max), t(max) and AUC(0- infinity ) values following the last dose were 296-691 nmol/l, 2-3 h, and 2911-6286 nmol h/ml, respectively. V(z)/F, CL/F and t(1/2z) values were 0.47-2.66 l/kg, 0.064-0.156 l/h/kg, and 3.0-16.3 h, respectively. CSF concentrations at steady state varied between 22.3 nmol/ml and 64.7 nmol/ml. Patients who had treatment failure tended to have lower plasma and CSF DFMO concentrations than those who had successful treatment. CONCLUSION: Oral DFMO at the dose of 125 mg/kg body weight given every 6 h for 14 days may not produce adequate therapeutic plasma and CSF levels for patients with late-stage T.b. gambiense sleeping sickness.

High-performance liquid chromatographic method for determination of 2-difluoromethyl-DL-ornithine in plasma and cerebrospinal fluid.

A simple, sensitive, selective and reproducible method based on anion-exchange liquid chromatography with post-column derivatisation was developed for the determination of eflornithine (2-difluoromethyl-DL-ornithine; DFMO) in human plasma and cerebrospinal fluid. The 1-alkylthio-2-alkyl-isoindoles fluorescent derivative of the drug was separated from the internal standard (MDL 77246A) on an anion-exchange column (PRP-X300, 250x2.1 mm, 7-microm particle size: Hamilton, USA), with retention times of 6.9 and 10.7 min, respectively. Fluorescence detection was set at 430/340 nm (emission/excitation wavelength). The elution solvent consisted of a solution of 30 mM potassium dihydrogen phosphate buffer (pH 2.2) and acetonitrile (50:50, v/v), running through the column at a flow-rate of 0.3 ml/min. The chromatographic analysis was operated at 37 degrees C. Sample preparation for either plasma or CSF (100 microl) was done by single-step protein precipitation with 20% trichloroacetic acid after incubation at 4 degrees C for 1 h. Calibration curves for plasma (100, 200, 400, 600, 800 and 1200 nmol/100 microl, and 10, 20, 40, 80, 120 and 160 nmol/100 microl for the high and low concentration range curves, respectively) and CSF (1, 2, 4, 8, 16, 32 nmol/100 microl) were all linear with correlation coefficients better than 0.999. The precision of the method based on within-day repeatability and reproducibility (day-to-day variation) at high concentration range was below 15%, whereas at low concentration range was below 20% (% coefficient of variations: %C.V.) Good accuracy was observed for both the intra-day or inter-day assays, as indicated by the minimal deviation of mean values found with measured samples from that of the theoretical values (below +/-15 and +/-20% at high and low concentration range, respectively. The limit of quantification was accepted as 0.1 nmol using 100-microl samples. The mean recovery for DFMO and the internal standard were greater than 95%. The method was free from interference from commonly used drugs including antimalarials and antihelminthics. The method appears to be robust and has been applied to a pharmacokinetic study of DFMO in patients with African trypanosomiasis following oral doses of Ornidyl (Aventis Pharma, Frankfurt, Germany) at 500 mg/kg body weight (125 mg q.i.d.) for 14 days.

[African trypanosomiasis in children treated with eflornithine. A case]. / Trypanosomiase africaine de l'enfant traitée par éflornithine. Un cas.

We report the case of a 14-year old African girl presenting with late-stage African T. gambiense trypanosomiasis. She was treated with eflornithine, an ornithine decarboxylase inhibitor which is a key enzyme in the biosynthesis of polyamine. Polyamines are essential to the multiplication of trypanosomes. Two treatment courses were necessary to achieve an apparent cure after one year; however, a longer follow up will be required to confirm whether or not the cure is permanent. Determination of drug concentrations in plasma and cerebrospinal fluid was performed during the second treatment course. Side-effects were easily controlled.