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. 2018 Jun;74(6):767-773.
doi: 10.1007/s00228-018-2434-4. Epub 2018 Mar 2.

Converting cyclosporine A from intravenous to oral administration in hematopoietic stem cell transplant recipients and the role of azole antifungals

Ferdows Atiq  1 , Edon Hameli  1 , Annoek E C Broers  2 , Jeanette K Doorduijn  2 , Teun Van Gelder  1   3 , Louise M Andrews  1 , Birgit C P Koch  1 , Jorie Versmissen  3 , Brenda C M de Winter  4
Affiliations

Converting cyclosporine A from intravenous to oral administration in hematopoietic stem cell transplant recipients and the role of azole antifungals

Ferdows Atiq et al. Eur J Clin Pharmacol. 2018 Jun.

Abstract

Purpose: Cyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals.

Methods: We retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration.

Results: We included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration.

Conclusions: In patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co-medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations.

Keywords: Cyclosporine A; Dose conversion; Ferdows Atiq and Edon Hameli contributed equally to this work.; Hematopoietic stem cell transplantation; Immunosuppression.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

All patients signed informed consent when undergoing HSCT, in which they gave permission for use of anonymized medical data by scientists.

Figures

Fig. 1
Fig. 1
Consort diagram. HSCT hematopoietic stem cell transplantation, IV1, IV2, IV3 first, second, last intravenous CsA administration before dose conversion, PO1, PO2, PO3 first, second, third oral administration after dose conversion
Fig. 2
Fig. 2
Mean CsA concentration and dosage. Data are presented as mean with 95% confidence interval. The dotted lines at 250 and 350 reflect the therapeutic range of CsA. IV1, IV2, IV3 first, second, last intravenous CsA administration before dose conversion, PO1, PO2, PO3 first, second, third oral administration after dose conversion
Fig. 3
Fig. 3
Mean dose-corrected CsA concentration. Each symbol reflects the mean dose-corrected CsA concentration at the illustrated time point
Fig. 4
Fig. 4
Distribution of CsA concentrations. Percentage of patients with subtherapeutic, therapeutic, and supratherapeutic CsA concentrations. IV1, IV2, IV3 first, second, last intravenous CsA administration before dose conversion, PO1, PO2, PO3 first, second, third oral administration after dose conversion
Fig. 5
Fig. 5
Change in eGFR. Each symbol reflects the eGFR at the illustrated time point. eGFR glomerular filtration rate, before IV1 before the first included intravenous CsA administration, after PO3 after the last included oral CsA concentration
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