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.