Day-to-day variability in azathioprine pharmacokinetics in renal transplant recipients

The intraindividual and the interindividual variability in the pharmacokinetics of azathioprine (Aza) and its main metabolite 6-mercaptopurine (6-MP) were investigated in 10 renal transplant patients on 2 consecutive days, after repeated oral doses of Aza. On the 1st study, the dose-adjusted Aza AUC (0-6 h) ranged from 8.4 to 129.1 ngh*ml-1/mg*kg-1, mean 41.4 (+/- 37.6) ngh*ml-1/mg*kg-1. The corresponding values for the dose-adjusted 6-MP AUC (0-6 h) ranged from 37.9 to 172.0 ngh*ml-1/mg*kg-1, mean 91.7 (+/- 50.7) ngh*ml-1/mg*kg-1. The absolute percentage intraindividual difference in Aza AUC (0-6 h) between the two days ranged from 1.2% to 256.6% (mean 64.7%), and for 6-MP AUC (0-6 h) from 5.9% to 98.5% (mean 49.8%). However, no statistically significant difference was found when comparing the pharmacokinetics on the 2 study days. The mean half-life of Aza was 1.7 h and of 6-MP 1.2 h. Impaired renal function did not seem to affect the pharmacokinetics. No correlation was found between the given dose of Aza and AUC (0-6 h) for Aza or 6-MP. A strong correlation was found between the concentrations of Aza and 6-MP obtained at 2 h after the oral dose and the corresponding AUCs (0-6 h) (Aza: r = 0.85, p < 0.001, n = 20; 6-MP: r = 0.9, p < 0.001, n = 20). We conclude that the intraindividual variability in Aza pharmacokinetics is marked, but it is less pronounced than the even larger interpatient variability found in this study and previously described.