Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias.
OBJECTIVE
The purpose of our study was to investigate the pharmacology of clofarabine and its triphosphate and the pharmacodynamic actions in circulating blasts obtained from acute leukemia patients who entered a Phase I clinical trial of clofarabine.


METHODS
Adults with refractory acute leukemias including lymphoblastic (ALL), myelogenous (AML) and chronic myelogenous leukemia in blastic phase (CML-BP) received clofarabine from 4 mg/m(2) to 55 mg/m2/day for 5 days as a 1-h i.v. infusion. A total of 26 of the 32 patients were studied for pharmacological investigations.


RESULTS
The maximum tolerated dose was 40 mg/m2/day for 5 days. Plasma pharmacology studies done in 25 patients indicate a linear increase in the plasma clofarabine concentration with increasing doses. At 40 mg/m2 the median plasma clofarabine level was 1.5 micro M (range, 0.42-3.2 micro M; n = 7). Cellular pharmacokinetic studies done at the end of the first clofarabine infusion in 26 patients appeared dose proportional but showed a wide variation in the concentrations of clofarabine triphosphate. At the maximum tolerated dose, the concentration was a median 19 micro M (range, 3-52 micro M). In the majority of cases, more than 50% of the analog triphosphate was present at 24 h after infusion. Compared with clofarabine triphosphate concentration, the endogenous level of dATP was low, resulting in a favorable ratio of analog triphosphate:normal deoxynucleoside triphosphate (dNTP) for incorporation into DNA. In association with the accumulation of triphosphate, there was a decrease in DNA synthesis. At 40- and 55-mg/m2 doses, the inhibition of DNA synthesis was maintained to 24 h.


CONCLUSIONS
Clofarabine at the maximum tolerated dose was effective with regard to inhibition of DNA synthesis and decline in circulating leukemia blasts. Given the clinical activity of clofarabine in adult acute leukemias, it is of interest to conduct a detailed characterization of the cellular pharmacology of clofarabine triphosphate and its relationship to clinical responses.
Gandhi
Varsha
V
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA. vgandhi@mdanderson.org
Kantarjian
Hagop
H
Faderl
Stefan
S
Bonate
Peter
P
Du
Min
M
Ayres
Mary
M
Rios
Mary Beth
MB
Keating
Michael J
MJ
Plunkett
William
W
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001087:Arabinonucleosides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077866:Clofarabine; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D020714:Maximum Tolerated Dose; D008956:Models, Chemical; D009360:Neoplastic Cells, Circulating; D009841:Oligonucleotides / Q000737:chemistry; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D013997:Time Factors
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D009841:Oligonucleotides; D000077866:Clofarabine; D004247:DNA