Summary
Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily x5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentrationtime curves yielded an average distribution half-life (t1/2α) of 0.60 h and a terminal half-life (t1/2β) of 9.3 h. The estimated plasma clearance was 9.07±3.77 l/h per m2 and the steady state volume of distribution, 96.2±26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r=-0.94, P<0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r=0.828; P<0.1). Aproximately 24%±3% of 2-FLAA was excreted renally over the 5-day course of drug administration.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- 2-FLAA-9-β-D:
-
arabinofuranosyl-2-fluoroadenine
- 2-FLAMP:
-
the 5'-monophosphate of 2-FLAA, also known as fludarabine phosphate
- AUC:
-
area under the curve
- AGC:
-
absolute granulocyte count
- TPC:
-
total plasma clearance
- Vdss :
-
volume of distribution at steady state
- Vd:
-
volume of distribution
- Creat Cl:
-
creatinine clearance
- SGOT:
-
serum glutamic-oxaloacetic transaminase
- WBC:
-
peripheral white blood cell count
References
Avramis VI, Plunkett W (1983) 2-Fluoro-ATP: A toxic metabolite of 9-β-D-arabinosyl-2-fluoroadenine. Biochem Biophys Res Commun 113: 35–43
Boxenbaum HG, Riegelman S, Elashoff RM (1974) Statistical estimations in pharmacokinetics. J Pharmacokin Biopharm 2: 123–148
Brockman RW, Schabel FM Jr, Montgomery JA (1977) Biologic activity of 9-β-D-arabinofuranosyl-2-fluoroadenine, a metabolically stable analog of 9-β-D-arabinofuranosyladenine. Biochem Pharmacol 26: 2193–2196
Brockman RW, Cheng Y-C, Schabel FM Jr, Montgomery JA (1980) Metabolism and chemotherapeutic activity of 9-β-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence of its phosphorylation by deoxycytidine kinase. Cancer Res 40: 3610–3615
Hutton JJ, Von Hoff D, Kuhn J, Phillips J, Hersh M, Clark G (1984) Phase I clinical investigation of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-monophosphate (NSC 312887), a new purine antimetabolite. Cancer Res 44: 4183–4186
Jusko W (1980) Guidelines for collection and pharmacokinetic analysis of drug disposition data. In Evans WE, Schentag JJ, Jusko WJ: Applied pharmacokinetics. Applied Therapeutics, San Francisco, pp 639–680
Malspeis L, De Souza JJV, Staubus AE, Neidhart JA, Grever MR (1984) Pharmacokinetics of 2-F-Ara-AMP in man during a phase I clinical trial. Investigat New Drugs 2: 116
Metzler CM, Elfring GL, McEwen AJ (1976) A users' manual: NONLIN and associated programs, Upjohn, Kalamazoo
Noker PE, Duncan GF, El Dareer SM, Hill DL (1983) Disposition of 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-phosphate in mice and dogs. Cancer Treat Rep 67: 445–446
Plunkett W, Chubb S, Alexander L, Montgomery JA (1980) Comparison of the toxicity and metabolism of 9-β-D-arabinofuranosyl-2-fluoroadenine and 9-β-D-arabinofuranosyladenine in human lymphoblastoid cells. Cancer Res 40: 2349–2355
Von Hoff DD, Coltman CA, Forseth B (1981) Activity of mitoxantrone in a human tumor cloning system. Cancer Res 41: 1853–55
Yamaoka K, Nakagawa T, Uno T (1978) Application of Akaike's information criterion (AIC) in evaluation of linear pharmacokinetic equations. J Pharmacokin Biopharm 6: 165–175
Author information
Authors and Affiliations
Additional information
This study was supported by contract NCI N01-CM-27542, NIH grant RR-01346 and by the VA Research Service.
Rights and permissions
About this article
Cite this article
Hersh, M.R., Kuhn, J.G., Phillips, J.L. et al. Pharmacokinetic study of fludarabine phosphate (NSC 312887). Cancer Chemother. Pharmacol. 17, 277–280 (1986). https://doi.org/10.1007/BF00256699
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00256699