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

Abstract

BackgroundCiclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune® Injection (Sandimmune®), uses Cremophor® EL as emulsifying excipient. Cremophor® EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock.ObjectivesThe primary objective was to assess if CicloMulsion®, a Cremophor® EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune®, and the secondary objective was to compare the tolerability profiles of the two preparations.MethodsThis 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.ResultsThe geometric mean ratios for CicloMulsion®/Sandimmune® (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC0–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 Cmax (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®. No serious adverse events were recorded after treatment with CicloMulsion®.ConclusionWe have assessed the pharmacokinetics and tolerability of a new Cremophor® EL-free lipid emulsion of ciclosporin, CicloMulsion®, compared to Sandimmune®. The proportion of adverse events was significantly higher for the Cremophor® EL-based product Sandimmune®. We conclude that CicloMulsion® is bioequivalent to Sandimmune® and exhibits fewer adverse reactions.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction

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Impact of cyclosporine A use in the prevention of reperfusion injury in acute myocardial infarction: A meta-analysis

“…However, the recently published CYCLE study, which used the Sandimmune formulation, failed to show a significant difference in primary endpoint (resolution of ST-segment ≥ 70%) [20]. The CicloMulsion preparation has been found to have similar pharmacokinetics and rather fewer adverse effects compared to Sandimmune preparation [25]. A study done on patients undergoing coronary artery bypass grafting surgery found no significant difference between the peak troponin T in CsA and placebo groups, except for the high-risk group with prolonged surgery -it showed that the extent of perioperative myocardial infarction was reduced in high-risk CsA patients [26].…”

Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury

“…We have previously shown bioequivalence between cyclosporine formulations in humans. 54 Piglets were randomized to 20 mg/kg/day (i.v.) of either the NeuroSTAT or Sandimmune formulation of cyclosporine ( N = 3/group).…”

“…NeuroSTAT ® is a novel lipid emulsion containing cyclosporine that differs from the Sandimmune formulation, which contains the solubilizer, Kolliphor EL (previously named Cremophor EL), which is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock. 54 Further, a secondary aim was to perform a systematic pharmacokinetics (PK) evaluation in order to create a bridge between the existing pre-clinical studies, primarily in rodents, and human clinical trials for TBI.…”