Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

Background: The circadian variation of clinical pharmacokinetics of tacroli mus in kidney transplant recipients receiving continuous intravenous admini stration has not been clarified. The aim of this study was to evaluate the circadian variation of this drug in continuous intravenous administration, with regard to the dosing scheme for conversion from intravenous to oral th erapy. Methods: The blood concentration-time curve was studied in 10 living-relate d kidney transplant recipients, aged 18-51 years (mean, 36.5 years), I day before operation for preoperative oral administration, the third postoperat ive day for continuous intravenous administration and the sixth postoperati ve day at the conversion from intravenous to oral therapy. Results: Although the total body clearance of daytime was slightly higher t han that of night-time, the intravenous tacrolimus infusion maintained an a dequate therapeutic blood concentration for 24 h. There were significant di fferences between the preoperative and the postoperative state in the area under the curve, total body clearance and bioavailability for the oral admi nistration. The mean absolute bioavailability was 17.7% in preoperative and 11.1% in postoperative state, respectively and a large interindividual var iation was confirmed in this parameter, which was 7.0-27.2% for preoperativ e and 6.4-22.0% for postoperative area under the curve, respectively. Conclusion: This study proposes that intravenous administration is a safe a nd appropriate method to achieve the required blood concentration in patien ts with various tacrolimus metabolism in the early post-transplant period. As the oral tacrolimus absorption was found to be variable between preopera tive and postoperative states in identical patients, the conversion dosage cannot be calculated from preoperative oral or postoperative intravenous ph armacokinetics. Frequent blood concentration monitoring is needed to ensure safe treatment.