[Effect of diltiazem on concentration of cyclosporin metabolites in Sandimmune and Neoral treated kidney transplant patients].
BACKGROUND
Diltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation.


METHODS
Fifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n = 17), with nifedipine (II, n = 17) and without calcium channel blockers (III, n = 17). Nine patients in each group received Sandimmun and 8 patients Neoral. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels.


RESULTS
The cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (-43%) and group III (-33%; p < 0.0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0.0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0.0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral were compared with those receiving Sandimmun within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun application than after Neoral. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun or Neoral. The incidences of acute rejection were lower in group I (17.6%) than in the other groups (II: 52.9%; III: 41%).


CONCLUSIONS
Diltiazem significantly reduced the necessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun to a larger extent than in patients taking Neoral. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun or Neoral were found.
Sperschneider
H
H
Klinik für Innere Medizin IV, Friedrich-Schiller-Universität Jena.
Wagner
C
C
Korn
A
A
Christians
U
U
D000328:Adult; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004110:Diltiazem / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009543:Nifedipine / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004110:Diltiazem; D009543:Nifedipine