6-Thioguanine in children with acute lymphoblastic leukaemia: influence offood on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations

Aims Since relatively little is known about the pharmacokinetics of 6-thiog uanine (6TG) in children receiving 6-thioguanine for maintenance therapy of acute lymphoblastic leukaemia (ALL), we studied plasma drug concentrations under standardized conditions and investigated the effect of food on paren t drug pharmacokinetics and the accumulation of the active metabolites 6-th ioguanine nucleotides (6-TGNs) in red cells. Methods Single oral doses of 40 mg of 6-TG were administered both in the fa sting and fed state to children with ALL. Pharmacokinetic sampling was perf ormed up to 6 h post dose. Daily oral doses of 40 mg m of 6-TG were adminis tered both fasting and after food over two 4 week periods. Twice weekly sam ples were taken for metabolite concentrations. The study design was cross-o ver with each child receiving dosing in either fasted or after food over a 4 week period in each phase. Results Eleven patients were studied. A wide interindividual variation in C -max (median 313 pmol ml(-1), range 51-737) and AUC (median 586 pmol ml(-1) h, range 156-1306) was observed in the fasted state. Concomitant food admi nistration resulted in a significant reduction in C-max (median 71 vs 313 p mol ml(-1), P = 0.006, CI from 36 to 426), AUC (median 200 vs 586 pmol ml(- 1) h, P = 0.006, 95% CI from 109 to 692), and time to reach C-max (median 1 .5 vs 3 h, P = 0.013, 95% CI from 0.74 to 2.73). There was no difference in the steady state concentration of red cell 6-TGNs observed after a 4 week period of 6-TG administered fasting or after food. Conclusions Children with ALL demonstrate significant interindividual varia tion in 6-TG pharmacokinetics. Although there would appear to be a reductio n in parent drug C-max and AUC with food there was no difference in 6-TGN c oncentrations after 4 weeks of 6-TG. Taking the drug on an empty stomach ma y not be necessary.