Background – Description of the Product
Intravenous cisplatin is one of the most widely-used chemotherapies in lung cancer. This is despite the drug’s high cumulative toxicity (mostly in the kidneys), which can become life threatening for patients and leads to treatment interruption. InhaTarget Therapeutics has developed a technology that allows delivery of cisplatin by means of a dry powder inhaler (DPI). This approach would sharply reduce the severe systemic toxicities of chemotherapy and increase anticancer efficacy, increasing the therapeutic ratio.
The DPI technology allows high cisplatin doses to be deposited in the lungs, which leads to more intense local therapeutic responses and low systemic toxicities. Doses are delivered in a relatively short time. DPI also suppress the large environmental contamination by the aerosol encountered with nebulizers, which are the only inhaler type already evaluated in clinical trials, up to Phase Ib/IIa, for nebulized cisplatin. DPI chemotherapy will be used in combination with other treatment modalities, e.g. immunotherapy, conventional chemotherapy, or surgery.
This technology gives DPI formulations that allow controlled release and prolonged retention of cisplatin in the lungs and the delivery of high local cisplatin doses with low lung fluid/tissue Cmax. This last point is significant as high lung fluid/tissue Cmax have been responsible for poor local tolerance in clinical studies involving nebulized chemotherapy.
Cisplatin is contained in tailored DPI formulations composed with excipients potentially safe for inhalation (e.g. triglycerides, PEG).
The development of this innovative treatment is currently at the preclinical stages of toxicity and efficacy studies in animal models, i.e. rodents and non-rodents.
- The DPI formulations have presented high cisplatin contents (~50%) and good aerodynamic properties, with fine particle fractions (FPF) of 40-50%.
- A sustained-release profile of cisplatin was obtained for up to 24 h in simulated lung fluids in vitro. This profile was achieved by means of a lipid matrix composed of triglycerides.
- The sustained-released DPI formulation prolonged drug platinum retention to up to 7 h in mouse lungs after pulmonary administration.
- The AUC in the lungs increased 11-fold with the sustained-released DPI formulation, compared to the same cisplatin dose administered as an IV solution. This favourable pharmacokinetic profile was demonstrated by the targeting efficiency (i.e. ratio of the AUC in the lungs to the sum of AUC in untargeted organs) and targeting advantage (i.e. ratio of the AUC in the lungs following inhalation to following IV administration) of the sustained-released DPI formulation compared with the same IV dose of cisplatin, i.e. values of 1.6 vs 0.09 and 10.9 vs 1, respectively.
- Low inflammation and cytotoxicity were observed in broncho-alveolar lavage fluids (BALF) following the inhalation of the sustained-released DPI formulation in healthy mice. There were significant neutrophil recruitment, non-statistically significant (NS) decrease in total cell number, NS increase in IL-6 concentrations and similar total protein, IL-1β and TNF-α concentrations and LDH activity, compared with non-treated control mice. This low local toxicity was directly imputable to cisplatin and not to the vehicle (i.e. the excipients as a powder).
- The sustained-released DPI formulation allowed similar in vivo tumour growth inhibition as IV cisplatin but at half cisplatin dose (0.5 vs 1 mg/kg, respectively) in an aggressive murine lung cancer model.
- Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties
V. Levet, R. Merlos, R. Rosière, K. Amighi, N. Wauthoz. Int. J. Pharm., 517, 359-372 (2017).
- Development of controlled-release cisplatin dry powders for inhalation against lung cancers
V. Levet, R. Rosière, R. Merlos, L. Fusaro, G. Berger, K. Amighi, N. Wauthoz. Int. J. Pharm., 515, 209-220 (2016).
- Tolerance of Cisplatin Dry Powders for Inhalation and Efficacy on an Orthotopic Grafted Lung Tumor Preclinical Model
V. Levet, R. Rosière, J. Hecq, I. Langer, K. Amighi, N. Wauthoz, RDD Europe 2017, Vol 2, 335-340 (2017)