Intranasal bioavailability is estrous-cycle regulated: Davunetide as a case study

The investigational drug davunetide is a small active fragment of activity-dependent neuroprotective protein (ADNP), regulating and being regulated by sex hormones. Mutations in ADNP sex-dependently dysregulate microtubules/mitochondria/unfolded protein response/autophagy/neurogenesis, leading to tauopathy, and are corrected by the microtubule-protecting, davunetide. The striking sex differences discovered in mice, coupled with multiple failures of clinical trials mixing the sexes in devastating tauopathies, emphasize the need for a paradigm-shifting approach towards sex-specific brain medicine. Indeed, the Tau-targeting davunetide has previously demonstrated sex-dependent clinical efficacy across diverse populations of neurodegenerative tauopathies and neuronal decline (e.g., Alzheimer's disease, progressive supranuclear palsy, and post-coronary artery bypass grafting [CABG] surgery), suggesting differences in drug bioavailability. Here, performing fluorescent davunetide bioavailability experiments via in vivo imaging in mice, we discovered sex-specific estrous-cycle-dependent brain bioavailability. Thus, females showed significantly greater head/body bioavailability than their male counterparts, especially during proestrus and estrus, corresponding to the highest estrogen levels, and extended to comparisons in females within the estrous cycle. In a human population of healthy adults, analysis of plasma pharmacokinetics following intranasal davunetide administration trended toward higher peak plasma concentrations in women and longer half-life in men, consistent with the preclinical findings and previous clinical trials. In the broader context, while considering our study limitation and the fact that davunetide is an investigational drug, we maintain that sex-specific brain medicine should become a central focus of precision medical investigation required for maintaining better health.