Pharmacokinetic interaction between oral cyclosporin and mibefradil in stabilized post-renal-transplant patients.
BACKGROUND
The potential for interaction between oral cyclosporin (Sandimmun) and the new calcium antagonist mibefradil was assessed as part of the clinical development of the new compound.


METHODS
Six stable renal transplant patients on long-term, oral, twice-daily (Q 12 H) cyclosporin (CsA) therapy received 25 mg mibefradil on Day 1, followed by 50 mg once daily for 5 or 6 days. At baseline, as well as on the last day of mibefradil dosing, complete steady-state CsA blood concentration-time profiles were characterized over a dosing interval.


RESULTS
Mibefradil led to mean increases in minimum and maximum CsA blood concentrations and area under the curve of CsA by 2.7-, 2.1-, and 2.3-fold, respectively (all significantly different from CsA alone, P < 0.02). Mibefradil is therefore associated with a clinically relevant increase in CsA blood concentrations. The mechanism of elevation of CsA blood concentrations is probably mibefradil and/or metabolite inhibition of the cytochrome P-450 isoenzyme 3A4. CsA had no clinically significant effect on mibefradil plasma concentrations.


CONCLUSIONS
These results confirm previous findings of cytochrome P-450 3A4 inhibition by mibefradil and suggest that, for patients receiving CsA, its dose must be adjusted and its plasma concentration must be monitored when adding or stopping mibefradil.
Spoendlin
M
M
Division of Nephrology, University of Basel, Kantonsspital, Switzerland.
Peters
J
J
Welker
H
H
Bock
A
A
Thiel
G
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D016572:Cyclosporine