Infectious Disease Research Program, Center for Bone Marrow Transplantation, Department of Pediatric Hematology/Oncology, University Childrens Hospital, Domagkstrasse 9a, 48129 Münster, Germany
Received 6 October 2003; accepted 13 October 2003
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Abstract |
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Keywords: antifungals, CYP450 isoenzymes, graft-versus-host disease
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Introduction |
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Case report |
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The patients course during the conditioning regimen and following marrow transplantation was essentially uncomplicated. She was discharged to the outpatient clinic on day +30 with regenerating haematopoiesis, complete donor chimerism and a stable dose of 2.8 mg/kg ciclosporin A given in two equally divided daily doses. Concomitant medication included voriconazole 200 mg twice a day, valaciclovir 500 mg twice a day and trimethoprimsulfamethoxazole 160 mg twice a day, twice weekly, for a body weight of 48 kg.
Because of steadily rising -glutamyltransferase and, ultimately, alkaline phosphatase (AP) values, but only mild increases in hepatic transaminases (serum glutamic pyruvic transaminase and serum glutamic-oxalic transaminase less than twice the upper limit of normal) and normal serum bilirubin and stable serum creatinine (0.81.1 mg/dL), voriconazole was stopped on day +56 due to presumed hepatotoxicity (Figure 1). Immediately after the discontinuation of voriconazole, there was a significant drop in ciclosporin A trough levels from stable concentrations in the range of 150184 ng/mL (mean 171.2) to 56111 ng/mL (mean 83.6; P = 0.01 by MannWhitney U-test). Since ciclosporin A trough concentrations may vary from day to day and the patient continued to do well, without any evidence of graft-versus-host disease (GvHD), no drugdrug interaction was considered and no dosage adjustment was initiated. Following improvement of liver function tests (LFTs), voriconazole was reinstituted on day +74. Ciclosporin A trough levels returned to their prior concentration range (126144 ng/mL, mean 134.5; P = 0.01 in comparison to ciclosporin A levels during discontinuation of voriconazole by MannWhitney U-test) and LFTs remained stable. Ciclosporin A was tapered starting on day +88 and discontinued at around day +130. The patient is now on day 160 post-transplantation in continued haematological remission, is doing well and continues to receive voriconazole owing to residual abnormalities on thoracic computed tomography scan.
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Discussion |
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The effects of voriconazole on the pharmacokinetics of ciclosporin A have been investigated in kidney transplant patients in a randomized, double-blind crossover study. Concomitant administration of voriconazole resulted in a 1.7-fold increase in the mean AUC of ciclosporin A along with similar increases in ciclosporin A trough concentrations. Moreover, a considerable number of patients experienced adverse events attributable to ciclosporin A toxicity during voriconazole treatment and prematurely discontinued it.5 In patients following allogeneic haematopoietic stem cell transplantation, the interaction between voriconazole and ciclosporin A has not been systematically studied to this date. However, it is highly relevant for clinical practice, since voriconazole is increasingly used as antifungal treatment in this complex setting. Voriconazole may be added to ciclosporin A, leading to potentially toxic ciclosporin A concentrations in blood and enhanced toxicity. Vice versa, as in the presented case, voriconazole may be withdrawn for various reasons, resulting in inadequate exposure of the post-transplant patient to ciclosporin A and increased risk for the onset of potentially life-threatening GvHD.
Thus, similar to itraconazole and fluconazole,4 clinically relevant pharmacokinetic interactions can occur with the concomitant use of voriconazole and ciclosporin A in haematopoietic stem cell transplant recipients. Close monitoring of ciclosporin A blood levels and appropriate dosage adjustments are mandatory when voriconazole is added to ciclosporin A or when voriconazole is discontinued following concomitant treatment with both drugs.
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Footnotes |
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References |
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2
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Pearson, M. M., Rogers, P. D., Cleary, J. D. et al. (2003). Voriconazole: a new triazole antifungal agent. Annals of Pharmacotherapy 37, 42032.
3
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Roffey, S. J., Cole, S., Comby, P. et al. (2003). The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog and human. Drug Metabolism and Disposition 31, 73141.
4 . Groll, A. H., Gea-Banacloche, J. C., Glasmacher, A. et al. (2003). Clinical pharmacology of antifungal compounds. Infectious Disease Clinics of North America 17, 15991.[ISI][Medline]
5 . Romero, A. J., Pogamp, P. L., Nilsson, L. G. et al. (2002). Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clinical Pharmacology and Therapeutics 71, 22634.[ISI][Medline]