A PEDIATRIC PHASE-I TRIAL AND PHARMACOKINETIC STUDY OF THIOGUANINE ADMINISTERED BY CONTINUOUS IV INFUSION

Citation
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
Citations number
24
Categorie Soggetti
Oncology
Journal title
ISSN journal
10780432
Volume
3
Issue
5
Year of publication
1997
Pages
713 - 717
Database
ISI
SICI code
1078-0432(1997)3:5<713:APPTAP>2.0.ZU;2-Z
Abstract
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.