A randomized, open-label, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults.
BACKGROUND
Tacrolimus is a macrolide immunosuppressant used in transplantation. It has been shown to have a comparable therapeutic effect and a low adverse drug reaction profile relative to cyclosporme.


OBJECTIVE
The present study compared the pharmacokinetics of twice-daily doses of 2 tacrolimus formulations used in clinical practice in Korea: a conventional (reference) formulation and a more recently developed (test) formulation. The bioavailability of the 2 formulations was evaluated based on the requirement of 20% deviation at a power of 80%.


METHODS
This study had a randomized, open-label, 2-period, crossover, non-inferiority design. There was a 96-hour treatment period for each formulation, with a 3-week washout period between formulations. Each healthy adult subject received two 1-mg capsules of the reference or test formulation of tacrolimus twice daily (morning and evening), for a total daily dose of 4 mg. Blood samples were obtained during the 96-hour period after the first dose in each treatment period, with tolerability assessments performed up to 2 weeks after the first dose in each period. The primary pharmacokinetic parameters were C(max) and AUC from time 0 to the last measured concentration and extrapolated to infinity. Secondary pharmacokinetic parameters were T(max), t(1/2), C(min0-24), AUC(0-24), and C(96).


RESULTS
The study enrolled 29 healthy Korean volunteers (22 men, 7 women; mean [SD] age, 29 [7] years; age range, 20-51 years; mean weight, 66 [10] kg; mean height, [171 17] cm). All volunteers completed both treatment periods. The 90% Cls for the ratios of the pharmacokinetic parameters (test:reference drug) were 119.25-161.29 for C(max), 95.29-129.04 for AUC(0-t), and 95.63-131.42 for AUC(0-infinity). Based on the 80% to 125% bioequivalence criterion, these results indicated that pharmacokinetic exposure to the test drug was not inferior to that of the reference drug. Both formulations were well tolerated, with no serious adverse events reported.


CONCLUSIONS
In these healthy Korean adults, there were no statistically significant differences between the pharmacokinetic parameters of the more recently developed oral formulation of tacrolimus and the conventional formulation.
Park
Kyungsoo
K
Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.
Kim
Yu Seun
YS
Kwon
Kwang-Il
KI
Park
Min Soo
MS
Lee
Yoon Jung
YJ
Kim
Kyung Hwan
KH
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D002853:Chromatography, Liquid; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007723:Korea; D008875:Middle Aged; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency
D002214:Capsules; D007166:Immunosuppressive Agents; D016559:Tacrolimus