Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease.
6-Thioguanine (6-TG) seems to be an attractive alternative in both AZA- and 6-MP-intolerant and -resistant IBD populations. However, little is known of 6-TG pharmacokinetics, metabolite levels, and their correlation with drug efficacy and toxicity in IBD patients. This study reports the 6-TG pharmacokinetics in a population of IBD patients and the predictive value of metabolite concentrations. Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations were measured in 28 IBD patients at t = 1, 2, 4, and 8 weeks after starting 6-TG, 20 mg once daily. Outcome measures included mean 6-TGN concentrations (+/-95% confidence interval [CI95%]) and their associations with TPMT genotype, 6-TG dose, and hematological, hepatic, pancreatic, and efficacy parameters during the 8 week period. Steady-state 6-TGN concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days, and measured 856 (CI95% 715-997) pmol/8 x 10 RBCs. Large interpatient variability occurred at all time-points. No correlation was found between steady-state 6-TGN concentrations and drug dose per kilogram body weight. No significant differences in 6-TGN concentrations were found between patients with adverse events and patients without any event. Also, mean 6-TGN concentrations did not differ in patients with active disease versus patients in remission. In IBD patients on 6-TG treatment, large interindividual differences in metabolite concentrations occur. In our population, we could not demonstrate a clear relationship between 6-TGN concentrations on one hand and toxicity and efficacy on the other, as exist in AZA- and 6-MP-treated patients.
Derijks
Luc J J
LJ
Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands. l.derijks@mmc.nl
Gilissen
Lennard P L
LP
Engels
Leopold G J B
LG
Bos
Laurens P
LP
Bus
Paul J
PJ
Lohman
Joseph J H M
JJ
van Deventer
Sander J H
SJ
Hommes
Daniel W
DW
Hooymans
Piet M
PM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013866:Thioguanine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000964:Antimetabolites, Antineoplastic; D013866:Thioguanine