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

• Published in: Biopharmaceutics & drug disposition Vol. 31; no. 1; pp. 72 - 81
• Main Authors: Yin, Wei, Karyagina, Elena V., Lundberg, Ante S., Greenblatt, David J., Lister-James, John
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2010
• Subjects: Administration, Oral; Adult; bioavailability; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; electrocardiography; Female; fludarabine phosphate; Half-Life; Heart Rate - drug effects; Heart Rate - physiology; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Chemical; pharmacokinetics; QT interval; Vidarabine - analogs & derivatives; Vidarabine - pharmacokinetics; Vidarabine Phosphate - analogs & derivatives; Vidarabine Phosphate - metabolism; Vidarabine Phosphate - pharmacokinetics
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.690

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/m2, n=14) or oral (40 mg/m2, 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/m2 IV and 40 mg/m2 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 © 2009 John Wiley & Sons, Ltd.