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.


CONCLUSIONS
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.
Na-Bangchang
K
K
Faculty of Allied Health Sciences, Thammasat University, Pathumtanee, Thailand. kesaratmu@yahoo.com
Doua
F
F
Konsil
J
J
Hanpitakpong
W
W
Kamanikom
B
B
Kuzoe
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014344:Trypanocidal Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D014347:Trypanosoma brucei gambiense; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000378:metabolism*
D014344:Trypanocidal Agents; D000518:Eflornithine