Effect of repeated dosing on the pharmacokinetics of oral fluconazole in bone marrow transplant patients

We examined the pharmacokinetics of fluconazole in II bone marrow transplant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27. No dose was given on day 2, day 14, and day 28 to allow the concentration-time data to be collected over 48 hours. The 24 hour urine was also collected, and fluconazole was analyzed in both plasma and urine by a high performance liquid chromatography. The plasma concentration-time data were best described by the one-compartment model with first-order absorption. The overall inter-day change and the difference between day 1 and day 27 in the rate constant for absorption (k(a)), peak plasma concentration (C-max), trough plasma concentration (C-min), time-to-peak (t(max)), area-under-the-curve 0-24 (AUC(0-24)), rate constant for elimination (k(e)), mean residence time after oral administration (MRTor), and fraction of the dose excreted unchanged in urine 24 hours (fu(24)) were significant (P less than or equal to 0.0029 and P less than or equal to 0.01, respectively). However, the difference between day 1 and day 13 wets significant (P less than or equal to 0.05) only in k(a), t(max), C-max, C-min, and AUC(0-24), and between day 13 and day 27 was significant (P less than or equal to 0.05) only in k(a), C-min, k(e), and MRTor. There was no significant inter-day change in the renal clearance. The significant (P less than or equal to 0.05) increases in C-max, C-min, and AUC(0-24), after the dose given on day 13 as compared with day 1, and in C-min, on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients. This perhaps should be taken into account when prescribing fluconazole to seriously ill patients.