Overview of the Nonclinical Safety Program for 1,1-Difluoroethane (HFA-152a) as a Low Global Warming Potential Metered Dose Inhaler Propellant
Mohar I1, Lewandowski TA1, Johnson S2, Corr SC2, & Leach C3
1Gradient, 600 Stewart Street, Suite 1900, Seattle, WA, USA
2Koura, Thornton Science Park, Pool Lane, Ince, Chester, CH2 4NU, United Kingdom
3Independent Consultant, Tijeras, NM, USA
Summary
Pressurized metered dose inhalers (pMDIs) deliver life-saving medicines with more than 800 million pMDIs produced annually. 1,1-Difluoroethane (HFA-152a) is being developed as a pMDI propellant and as a more environmentally sustainable alternative to current hydrofluoroalkane (HFA) propellants, with an approximate 90% reduction in global warming potential. HFA-152a is a gas at ambient temperature and pressure, has no intended or expected pharmacologic activity, and has been shown to be well tolerated and without adverse effects in a Phase 1 clinical study of HFA-152a administered via a pMDI. In this paper, we summarize the results of a comprehensive nonclinical safety program for HFA-152a to support clinical use in pMDIs. The nonclinical safety program showed that medical-grade HFA-152a caused no toxicity in mice, rats, or dogs, and no carcinogenicity in rats at delivered doses a minimum of 1800 times the anticipated clinical maximum daily exposure (MDE) for adults. HFA-152a caused no developmental or reproductive toxicity in rats or toxicity in juvenile rats at delivered doses greater than 2400 times the MDE. Furthermore, the results of specialized safety pharmacology studies showed that clinical use of HFA-152a would not pose a meaningful risk of respiratory sensitization or cardiac sensitization. Lastly, the results of bacterial mutagenicity, in vitro micronucleus, and in vivo micronucleus assays did not show HFA-152a to be mutagenic or genotoxic. Overall, the current nonclinical safety program for medical-grade HFA-152a supports the safety of HFA-152a as a pMDI propellant for inhaled drugs intended for all patient populations and chronic daily use.