Unpredictable cyclosporin-fluconazole interaction in renal transplant recipients

Citation
K. Sud et al., Unpredictable cyclosporin-fluconazole interaction in renal transplant recipients, NEPH DIAL T, 14(7), 1999, pp. 1698-1703
Citations number
20
Categorie Soggetti
Urology & Nephrology
Journal title
NEPHROLOGY DIALYSIS TRANSPLANTATION
ISSN journal
09310509 → ACNP
Volume
14
Issue
7
Year of publication
1999
Pages
1698 - 1703
Database
ISI
SICI code
0931-0509(199907)14:7<1698:UCIIRT>2.0.ZU;2-O
Abstract
Background. Cyclosporin (CsA) is metabolized primarily in the liver by cyto chrome P-450 enzymes. Concomitant use of fluconazole can increase CsA conce ntrations by inhibiting this enzyme system and the effect seems to be dose dependent, with no interaction noted when fluconazole is used in a dose of 100 mg/day. Two previous investigations studying this inter-action while us ing higher doses of fluconazole have provided inconsistent results. Recomme ndations advising an empirical 50% CsA dosage reduction in these patients h ave not been tested iri a prospective trial. Methods. We studied six renal transplant recipients on CsA immunosuppressio n in a prospective, unblinded, crossover trial. Baseline renal functions, C sA area under the curve (AUC), C-max, C-min, CsA clearance, and T-max were compared with those 2, 4 and 7 days after starting fluconazole orally in a dose of 200 mg/day. From day 8 onwards, patients reduced CsA dose by 50% an d the above parameters were repeated on day 14. Results. CsA AUC increased from 2887+/-1729 ng.h/ml on day 0 to 3842+/-1975 ng.h/ml on day 2 (P<0.05), 4750+/-1718 ng.h/ml on day 4 (P < 0.01) and the n decreased to 4052+/-1687 ng.h/ml on day 7 (P<0.01). Following CsA dose re duction by 50%, the mean AUC decreased significantly to 2330+/-1602 ng.h/ml (P<0.01). The C-max showed a significant increase from 701+/-345 ng/ml on day 0 to 941+/-326 ng/ml (P<0.01) on day 4 but decreased from 768+/-292 ng/ ml on day 7 to 498+/-289 ng/ml on day 14, P<0.01. The mean C-min increased from 207+/-138 ng/ml on day 0 to 274+/-168 ng/ml on day 4. No significant c hanges were observed in CsA clearance and T-max. On repeated-measurement AN OVA, only the AUC and C-max on day 4 of fluconazole were significantly high er than day 0 (P<0.001). There was a large interindividual variability in t he degree of drug interaction between patients. Conclusions. Fluconazole given orally in a dose of 200 mg/day is associated with significant increase in bioavailability of CsA. The maximum effect oc curs on day 4 after starting fluconazole. Although repeated monitoring of C sA C-min is convenient as opposed to repeated determination of AUC, changes in C-min may not be sensitive enough to pick up this interaction. The incr ease in bioavailability of CsA is unpredictable in individual patients and all patients should be monitored with AUC near day 4 of treatment to guide CsA dosage reductions.