Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate.

Abstract

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.

• Authors: Wei Yin, Elena V Karyagina, Ante S Lundberg, David J Greenblatt, John Lister-James
• Journal: Biopharmaceutics & drug disposition (Biopharm Drug Dispos) Vol. 31 Issue 1 Pg. 72-81 (Jan 2010) ISSN: 1099-081X [Electronic] England
• PMID: 19862681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vidarabine Phosphate
• fludarabine phosphate
• Vidarabine
• fludarabine

Topics

• Administration, Oral
• Adult
• Biological Availability
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Synergism
• Female
• Half-Life
• Heart Rate (drug effects, physiology)
• Humans
• Male
• Metabolic Clearance Rate
• Middle Aged
• Models, Chemical
• Vidarabine (analogs & derivatives, pharmacokinetics)
• Vidarabine Phosphate (analogs & derivatives, metabolism, pharmacokinetics)