Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor® EL

Background Ciclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro-and cardio-protection. The intravenous formulation currently on the market, Sandimmune (R) Injection (Sandimmune (R)), uses Cremophor (R) EL as emulsifying excipient. Cremophor (R) EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock. Objectives The primary objective was to assess if CicloMulsion (R), a Cremophor (R) EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune (R), and the secondary objective was to compare the tolerability profiles of the two preparations. Methods This was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed. Results The geometric mean ratios for CicloMulsion (R)/Sandimmune (R) (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC(0-last) (area under the blood concentration-time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for C-max (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80-1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune (R). No serious adverse events were recorded after treatment with CicloMulsion (R). Conclusion We have assessed the pharmacokinetics and tolerability of a new Cremophor (R) EL-free lipid emulsion of ciclosporin, CicloMulsion (R), compared to Sandimmune (R). The proportion of adverse events was significantly higher for the Cremophor (R) EL-based product Sandimmune (R). We conclude that CicloMulsion (R) is bioequivalent to Sandimmune (R) and exhibits fewer adverse reactions.