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Medizinische Klinik

, Volume 92, Issue 10, pp 589–596 | Cite as

Der Einfluß von Diltiazem auf die Konzentration von Cyclosporin-Metaboliten bei mit Sandimmun® und Neoral® behandelten nierentransplantierten Patienten

  • Heide Sperschneider
  • Constanze Wagner
  • Alexander Korn
  • Uwe Christians
Originalarbeit

Zusammenfassung

□ Hintergrund

Diltiazem reduziert die für therapeutische Blutspiegel erforderliche Cyclosporin-Dosis um 30 bis 40%. Der Effekt von Diltiazem auf die Pharmakokinetik von Cyclosporin nach Gabe von Sandimmun® ist bekannt, nicht dagegen, ob die Diltiazem-Cyclosporin-Interaktion durch die galenische Cyclosporin-Formulierung Neoral® beeinträchtigt wird.

□ Patienten und Methoden

51 stabile nierentransplantierte Patienten (19 Frauen, 32 Männer) wurden in eine prospektive, randomisierte, doppelblinde Studie einbezogen. Die Patienten wurden drei Behandlungsgruppen zugewiesen: mit Diltiazem (I, n=17), mit Nifedipin (II, n=17) und ohne Calciumblocker (III, n=17). Neun Patienten jeder Gruppe erhielten Sandimmun® und acht Patienten Neoral®. Die Blutspiegel von Cyclosporin und die Metaboliten AM1 und AM9 wurden über zwölf Wochen mittels HPLC gemessen. Die drei Behandlungsgruppen zeigten keinen Unterschied in bezug auf Alter, Geschlecht und Serumkreatinin. Die Cyclosporin-Dosierung wurde entsprechend dem Blutspiegel angepaßt.

□ Ergebnisse

Die erforderliche tägliche Cyclosporin-Dosis bis zum Erreichen des therapeutischen Blutspiegels war signifikant niedriger in Gruppe I (198,8±6,1 mg/Tag) im Vergleich zur Gruppe II (346,9 ± 10,2 mg/Tag; −43%; p < 0,0001) und Gruppe III (296,9 ± 6,7 mg/Tag; −33%, p < 0,0001). Die Cyclosporin-Konzentrationen im Blut lagen in allen Gruppen im therapeutischen Bereich, aber die Blutspiegel in Gruppe I zeigten eine viel geringere Variabilität. Die Konzentration des Metaboliten AM1 war nach Dosiskorrektur in Gruppe I signifikant höher, die von AM9 signifikant niedriger als in den Gruppen II und III (p < 0,0001). Zwischen den beiden Cyclosporin-Verabreichungsformen innerhalb der Gruppen gab es nach zwölf Wochen keinen Unterschied in der durchschnittlichen Dosierung und den Blutspiegeln von Cyclosporin. In Gruppe I war die Blutkonzentration von AM1 signifikant höher nach Sandimmun®-Gabe als nach Neoral®. Die Inzidenz von akuten Abstoßungen war in Gruppe I mit 17,6% niedriger als in den Gruppen II (52,9%) und III (41,2%).

□ Schlußfolgerung

Diltiazem reduziert signifikant die Cyclosporin-Dosis mit Konzentrationen im therapeutischen Bereich, führt zu stabileren Cyclosporin-Blutspiegeln und erhöht die Konzentration von AM1 besonders bei Patienten, die mit Sandimmun® behandelt werden. Darüber hinaus gab es keine signifikanten Unterschiede zwischen den beiden Darreichungsformen von Cyclosporin mit und ohne begleitend verabreichten Calciumantagonisten.

Schlüsselwörter

Nierentransplantation Diltiazem Cyclosporin-Métaboliten Sandimmun® Neoral® 

Effect of diltiazem on cyclosporine metabolites through blood concentrations after sandimmun® and neoral® in renal transplant patients

Summary

□ 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.

□ Patients and 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,%).

□ Conclusion:

Diltiazem significantly reduced the neccessary 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 takingNeoral®. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun® or Neoral® were found.

Key Words

Renal Transplantation Diltiazem Cyclosporin Metabolite Sandimmun® Neoral® 

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Copyright information

© Urban & Vogel 1997

Authors and Affiliations

  • Heide Sperschneider
    • 1
  • Constanze Wagner
    • 1
  • Alexander Korn
    • 2
  • Uwe Christians
    • 3
  1. 1.Klinik für Innere Medizin IV der UniversitätJena
  2. 2.Novartis AGNürnberg
  3. 3.Department of Biopharmaceutical Sciences, School of PharmacyUniversity of California at San FranciscoSan FranciscoUSA

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