Diltiazem-cyclosporin pharmacokinetic interaction--dose-response relationship

To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients.

Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day(-1). Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem.

Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day(-1)), the rate of increase slowed after 30-60 mg day(-1) but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0-12 h) and evening (12-24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ.

The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.