Published in:
01-04-2002 | Original Research Article
Pharmacokinetic Interaction Between Tacrolimus and Diltiazem
Dose-Response Relationship in Kidney and Liver Transplant Recipients
Authors:
Dr Terry E. Jones, Raymond G. Morris
Published in:
Clinical Pharmacokinetics
|
Issue 5/2002
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Abstract
Objective
To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in kidney and liver transplant recipients.
Design
Nonrandomised seven-period stepwise pharmacokinetic study.
Patients
Stable kidney (n = 2) and liver (n = 2) transplant recipients maintained on oral tacrolimus twice daily but not taking diltiazem.
Methods
Patients were treated with seven incremental dosages of diltiazem (0 to 180 mg/day) at ≥ 2-weekly intervals. At the end of each interval, 13 blood samples were taken over a 24-hour period to allow determination of morning (AUC12), evening (AUC12–24) and 24-hour (AUC24) areas under the concentration-time curve for tacrolimus, as well as AUC24 for diltiazem and three of its metabolites.
Results
There was considerable interpatient variability in tacrolimus-sparing effect. In the two kidney transplant recipients, an increase in tacrolimus AUC24 occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maximum increase in tacrolimus AUC24 occurred at the maximum diltiazem dosage used (180 mg/day), when the increase was 48 and 177%. In the two liver transplant recipients, an increase in tacrolimus AUC24 did not occur until a higher diltiazem dosage (60 to 120 mg/day) was given. The increase at the maximum diltiazem dosages used (120 mg/day in one and 180 mg/day in the other) was also lower (18 and 22%) than that exhibited by the kidney transplant recipients. The increase in tacrolimus AUC12 was similar to the increase in AUC12–24 when diltiazem was given in the morning only (dosages ≤60 mg/day). Hence, diltiazem affects blood tacrolimus concentrations for longer than would be predicted from the half-life of diltiazem in plasma.
Conclusions
The mean tacrolimus-sparing effect of diltiazem was similar in magnitude to the cyclosporin-sparing effect previously reported. Whether the lesser tacrolimus-sparing effect with diltiazem seen in the liver transplant recipients was due to functional differences in the transplanted liver is not known, but it was not due to lower plasma diltiazem concentrations. Diltiazem makes a logical tacrolimus-sparing agent because of the potential financial savings and therapeutic benefits. Because of interpatient variability, the sparing effect should be demonstrated in each patient and not merely assumed.