Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.
OBJECTIVE
Voriconazole is a broad-spectrum triazole antifungal agent under investigation for opportunistic infections that often target immunosuppressed patients. This study investigated the effect of voriconazole on the pharmacokinetics of cyclosporine (INN, ciclosporin).


METHODS
This was a randomized, double-blind, placebo-controlled, crossover study in kidney transplant recipients with stable renal function who were receiving cyclosporine (150-375 mg/d). During the first study period (7.5 days), subjects in group A received concomitant voriconazole (200 mg every 12 hours); group B received a matched placebo. After a washout period (>or=4 days), subjects were crossed over to the other treatment regimen.


RESULTS
In the 7 subjects who completed both regimens, concomitant administration with voriconazole resulted in a 1.7-fold increase in mean cyclosporine area under the plasma concentration-time curve within a dosage interval (AUC(tau); 90% confidence interval, 1.47 to 1.96). Cyclosporine maximum observed plasma concentration (C(max)) and the time to the first occurrence of C(max) (t(max)) were not affected in a clinically significant manner, but plasma trough concentration (C(min)) was higher in the presence of voriconazole than with placebo. The mean increase in cyclosporine C(min) in subjects who ceased to participate in the study was 2.48-fold (range, 1.88 to 3.03). There were 7 subjects who stopped participating in the study during voriconazole administration. Six of these subjects discontinued the study for reasons that were considered to be drug related, and the majority were attributable to increased cyclosporine levels. Although not serious, all causality-related adverse events were more frequent during voriconazole administration than during placebo administration.


CONCLUSIONS
Mean cyclosporine AUC(tau) increased 1.7-fold in the presence of voriconazole. Therefore, when voriconazole is initiated in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be halved and that blood cyclosporine concentrations be carefully monitored. When voriconazole is discontinued, blood cyclosporine concentrations should be monitored and the cyclosporine dose increased, if necessary.
Romero
Alain J
AJ
Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.
Le Pogamp
Patrick
P
Nilsson
Lars-Goran
LG
Wood
Nolan
N
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D016001:Confidence Intervals; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000188:drug therapy; D006801:Humans; D016030:Kidney Transplantation / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D010361:Patients / Q000706:statistics & numerical data*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D016572:Cyclosporine; D065819:Voriconazole