Bj. Kitchen et al., A PEDIATRIC PHASE-I TRIAL AND PHARMACOKINETIC STUDY OF THIOGUANINE ADMINISTERED BY CONTINUOUS IV INFUSION, Clinical cancer research, 3(5), 1997, pp. 713-717
Although mercaptopurine is the thiopurine antimetabolite predominantly
used in the treatment of childhood acute lymphoblastic leukemia (ALL)
, thioguanine (TG) is more potent than mercaptopurine in in vitro cyto
toxicity studies in human leukemic cell lines and leukemic cells from
patients with ALL, We conducted a pediatric Phase I trial of TG admini
stered as a continuous i,v, infusion (CIV), A pharmacokinetically guid
ed dose escalation was performed to define the dose rate of TG require
d to achieve a steady-state plasma concentration (C-ss) exceeding the
target concentration of 1 mu M, and then the maximum tolerated duratio
n of infusion of TG at this dose rate was defined, Eighteen patients (
median age, 18 years; range, 4-25 years) with refractory malignancies
(16 solid tumors and 2 ALL) were enrolled in this study, The starting
dose rate of 10 mg/m(2)/h administered for 24 h achieved an average C-
ss of 0.9 mu M (range, 0.7-1.2 mu M). Therefore, the dose rate was esc
alated to 20 mg/m(2)/h, which achieved an average C-ss of 4.1 mu M (ra
nge, 1.0-8.3 mu M). This disproportionate increase in the C-ss of TG s
uggested a capacity-limited (saturable) elimination process, and a pha
rmacokinetic model incorporating two compartments with capacity-limite
d elimination from ,the central compartment was developed to describe
the disposition of TG, The TG clearances (derived from model parameter
s) at the 10- and 20-mg/m(2)/h dose rates were 987 and 608 ml/min/m(2)
, respectively. Dose-limiting myelosuppression (absolute granulocyte c
ount < 500/mm(3) and platelet count < 25,000/mm(3)) was observed in tw
o of three patients treated with a dose rate of 20 mg/m(2)/h administe
red for 36 h, Administration of CIV of TG at 20 mg/m(2)/h for 24 h was
well tolerated in nine patients, Nonhematological toxicities included
nonneutropenic infections and mild, reversible changes in hepatic fun
ction tests, The recommended dose rate and duration for CIV of TG is 2
0 mg/m(2)/h for 24 h.