Pharmacokinetics of FK506 After Intravenous and Oral Administration in Patients Awaiting Renal Transplantation

Abstract

The authors examined the safety and pharmacokinetics of FK506, a new hepatically metabolized immunosuppressant, after single-dose intravenous (i.v.) infusion (20 micrograms.kg(-1) x 4 hours-1) and oral (80 micrograms/kg) administration in six nondialysis patients, aged 27 to 53 years, with chronic renal failure awaiting transplantation. A two-period, randomized, crossover study protocol was used with blood samples drawn for 72 hours after each dose and a washout period of 4 days. Whole-blood FK506 levels were determined using a standard, two-step, nonspecific enzyme immunoassay. There were no significant changes in vital signs, EKG, or complete laboratory test battery for any patient during the entire study period. No side effects were noted after i.v. or oral FK506 dosing. Mean +/- SD distribution half life was 0.9 +/- 0.2 hours, elimination half life (t1/2 beta) 33 +/- 8 hours, total body clearance (CL) 2.4 +/- 1.1 L/hour, and bioavailability 14 +/- 12%. There was no significant correlation between serum creatinine (Cr) and CL (r = 0.36) or between Cr and t1/2 beta (r = -0.30). It was found that FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing. An extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.

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“…The results are in accordance with previously published data obtained from pharmacokinetics studies performed in other kidney transplant recipients. Gruber and associates 22 have shown a clearance value of 2.4 L/h after oral administration of tacrolimus. Similarly, Velickovic and associates, 23 who performed a population pharmacokinetics study on 63 Serbian adult kidney transplant patients, found a typical mean value of tacrolimus clearance of 1.03 L/h.…”

Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

“…10,13 In some patients, the drug has a flat absorption profile and seems to be absorbed over most of the dosing interval. 13 Although the current recommendation is to initiate tacrolimus therapy orally, intravenous therapy is used in many institutes because of the various bioavailability of this drug. To achieve an adequate drug concentration, the initiation of tacrolimus therapy via the continuous intravenous route is probably a better method of administration.…”

“…14 The pharmacokinetics of tacrolimus have been clarified in healthy volunteers and liver and kidney transplant patients. [13][14][15][16] Several studies have been undertaken on the circadian changes of various drugs. 15 Pharmacokinetics due to circadian rhythms are affected by various factors, such as alteration in absorption and liver function.…”

“…In oral administration, tacrolimus has been shown to be rapidly absorbed, with a mean time-to-peak concentration of approximately 1-1.5 h. 8,13 In some patients, however, the drug may be absorbed over a prolonged period, resulting in a more flat absorption profile. The mean bioavailability has been reported as approximately 21%, although there is a large interindividual variability in this parameter.…”

“…8 However, there are large interindividual variations in the pharmacokinetics of tacrolimus from this and other studies. 9,10,13,14,16,19,20 It can be concluded that initiation of tacrolimus therapy via the intravenous route is a better method of administration. The conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics.…”