Pharmacokinetics and immune reconstitution following discontinuation of thiopurine analogues: Implications for drug withdrawal strategies.
J Crohns Colitis. 2018 Aug 27;:
Authors: Ben-Horin S, Van Assche G, Chowers Y, Fudim E, Ungar B, Picard O, Yavzori M, Kopylov U, Ren M, Chen MH, Peled-Potashnik Y, Gueta I, Eliakim R, Loebstein R, Markovits N
Introduction: Thiopurine analogues discontinuation is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant.
Objectives: To determine drug elimination and immune re-constitution following thiopurine cessation.
Methods: 6-thioguanine nucleotides (6-TGN) elimination kinetics were determined in 9 inflammatory bowel disease (IBD) patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 (TSST1) or anti-CD3 (OKT3)-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine (6MP), separately or combined.
Results: All patients discontinuing thiopurines displayed first order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days (IQR 5.9-8.4). Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent poly-clonal or Vβ2+-preferential stimulation. Contrarily, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation (p=0.008); whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered (p=0.9).
Conclusions: Upon 6MP/azathioprine discontinuation, 6TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.
PMID: 30169593 [PubMed – as supplied by publisher]