Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate.
The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25 mg/m(2), n=14) or oral (40 mg/m(2), n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (+/-SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3+/-4.0 vs 9.7+/-2.0 h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25 mg/m(2) IV and 40 mg/m(2) oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes.
Yin
Wei
W
Department of Clinical Pharmacology, Antisoma Research Limited, 300 Technology Square, Cambridge, MA 02139, USA. wei.yin@antisoma.com
Karyagina
Elena V
EV
Lundberg
Ante S
AS
Greenblatt
David J
DJ
Lister-James
John
J
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008956:Models, Chemical; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D014740:Vidarabine; C024352:fludarabine