Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguaninein children with acute lymphoblastic leukemia: a collaborative pediatric oncology branch, NCI, and Children's Cancer Group study

Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance ag ent, mercaptopurine (MP), suggesting that TG may be more efficacious than M P in the treatment of childhood ALL. As part of a pilot trial in which TG w as used in place of MP, we studied the plasma pharmacokinetics of oral TG a nd measured steady-state plasma and CSF TG concentrations during a continuo us intravenous infusion (CIVI) in children with newly diagnosed standard-ri sk ALL. Methods: Nine plasma samples were collected after each patient's fi rst 60 mg/m(2) oral TG dose during maintenance. CIVI TG (20 mg/m(2)/h over 24 h) was administered during the consolidation phase of therapy, and simul taneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythroc yte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. Results: After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46+/-0 .68 muM and the AUC ranged from 0.18 to 9.5 muM . h (mean 1.5 muM. h). Mean steady-state plasma and CSF TG concentrations during CIVI (n=33) were 2.7 and 0.5 muM, respectively. The mean (+/-SD) TG clearance was 935+/-463 ml/m in per m(2). Plasma TG concentrations did not correlate with erythrocyte TG N concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF, Conclusions: TG concentrations that are cytotoxic to hu man leukemia cell lines can be achieved in plasma after a 60 mg/m(2) oral d ose of TG and in plasma and CSF during CIVI of TG.