A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Abstract

Purpose: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT.

Methods: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib.

Results: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004).

Conclusions: Imatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered.

Keywords: Cyclosporine; Graft-versus-host disease; Hematopoietic stem cell transplantation; Imatinib.

Fig. 1

Average dose-corrected CsA concentration before and after initiation of imatinib. The average of all ratios of CsA concentration (ng/mL) divided by the used daily dose of CsA on that day (mg) before and after initiation of imatinib. Patients using *fluconazole 50 mg once daily; ^#fluconazole 400 mg once daily; ^voriconazole 200 mg twice daily, all the same dose before and after initiation of imatinib; ⁺fluconazole 400 mg once daily before and 200 mg once daily after initiation of imatinib