PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS: The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS: The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION: Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.
PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS: The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS: The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION: Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.
Authors: Yago Nieto; Peter Thall; Ben Valdez; Borje Andersson; Uday Popat; Paolo Anderlini; Elizabeth J Shpall; Roland Bassett; Amin Alousi; Chitra Hosing; Partow Kebriaei; Muzaffar Qazilbash; Erin Frazier; Alison Gulbis; Christina Chancoco; Qaiser Bashir; Stefan Ciurea; Issa Khouri; Simrit Parmar; Nina Shah; Laura Worth; Gabriela Rondon; Richard Champlin; Roy B Jones Journal: Biol Blood Marrow Transplant Date: 2012-05-27 Impact factor: 5.742
Authors: S M de Lange; K van der Born; J R Kroep; H A Jensen; P Pfeiffer; A Cleverly; C J van Groeningen; G J Peters Journal: Eur J Clin Pharmacol Date: 2005-11-10 Impact factor: 2.953
Authors: Liping Zhang; Vikram Sinha; S Thomas Forgue; Sophie Callies; Lan Ni; Richard Peck; Sandra R B Allerheiligen Journal: J Pharmacokinet Pharmacodyn Date: 2006-06-13 Impact factor: 2.745
Authors: Daniel Kozo; Matt W Ross; Justin Jarrah; Michael Barrett; Rebecca L Harney; Jodi B Courtney; Irina Baburina; Julianne L Holleran; Jan H Beumer; Godefridus J Peters; Richard J Honeywell; Salvatore J Salamone Journal: Ther Drug Monit Date: 2017-06 Impact factor: 3.681