Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate. Biopharmaceutics & drug disposition [Biopharm Drug Dispos] Journal article | | Title | Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate. | | Author(s) | Yin W, Karyagina EV, Lundberg AS, Greenblatt DJ, Lister-James J | | Institution | Departments of Clinical Pharmacology and Clinical Development, Antisoma Research Limited, 300 Technology Square, Cambridge, MA 02139, USA. | | Source | Biopharm Drug Dispos 2009 Oct 26. | | 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. Copyright (c) 2009 John Wiley & Sons, Ltd. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19862681 |
|
|
| |
Advertise on this site.
| | |
|
