Nephrology Dialysis Transplantation, Vol 14, Issue 7 1698-1703, Copyright © 1999 by Oxford University Press
K Sud, B Singh, V Krishna, K Thennarasu, H Kohli, V Jha, K Gupta and V Sakhuja
Background: Cyclosporin (CsA) is metabolized primarily
in the liver by cytochrome P-450 enzymes. Concomitant use of fluconazole
can increase CsA concentrations 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 interaction while using higher doses of fluconazole have
provided inconsistent results. Recommendations advising an empirical 50%
CsA dosage reduction in these patients have not been tested in a
prospective trial. Methods: We studied six renal
transplant recipients on CsA immunosuppression in a prospective, unblinded,
crossover trial. Baseline renal functions, CsA area under the curve (AUC),
Cmax, Cmin, CsA clearance, and Tmax 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% and the above parameters were
repeated on day 14. Results: CsA AUC increased from
2887±1729 ng.h/m on day 0 to 3842±1975 ng.h/mol on
day 2 (P<0.05), 4750±1718 ng.h/mol on day 4
(P<0.01) and then decreased to 4052±1687 ng.h/ml on day 7
(P<0.01). Following CsA dose reduction by 50%, the mean AUC
decreased significantly to 2330±1602 ng.h/ml (P<0.01).
The Cmax 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 Cmin increased from 207±138 ng/ml on day
0 to 274±168 ng/ml on day 4. No significant changes were
observed in CsA clearance and Tmax. On repeated-measurement ANOVA, only the
AUC and Cmax on day 4 of fluconazole were significantly higher than day 0
(P<0.001). There was a large interindividual variability in the
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 occurs on day 4 after starting fluconazole. Although
repeated monitoring of CsA Cmin is convenient as opposed to repeated
determination of AUC, changes in Cmin may not be sensitive enough to pick
up this interaction. The increase 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 reduction.
Key words: cyclosporin A; drug interaction;
fluconazole; transplantation
ORIGINAL ARTICLES
Unpredictable cyclosporin-fluconazole interaction in renal transplant recipients
Departments of Nephrology, Nuclear Medicine and Biostatistics, Postgraduate Institute of Medical Education and Research, Chandigarh, India, 160012; Corresponding author
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