B28-19 Pharmacokinetics, Pharmacodynamics and Safety of Sustained-release DHEA in Asthma

Rationale Asthma is sexually dimorphic with women being more affected than men in adulthood. The mainstay of treatment is glucocorticoids (GCs) which are not always effective and are known to suppress endogenous dehydroepiandrosterone (DHEA) production. Our preliminary data demonstrates a variety of protective DHEA effects on airway epithelial cell function and inflammatory responses. Therefore, we hypothesize that exogenous administration of DHEA will serve a protective role in severe asthma. We designed a pharmacokinetics (PK) and pharmacodynamics (PD) study to determine the optimal dose of DHEA for future studies. Methods To determine the dose and evaluate the safety and tolerability of Sustained-Release DHEA (SR-DHEA) we enrolled 9 asthma participants (5 males; median age 31 years (range 18-47)). A single dose of 50mg SR-DHEA was administered with serum DHEA-S measured at multiple times points over 12 hours. After a 7-day washout period, 50mg SR-DHEA twice daily was administered for 3 days with serum DHEA-S measured daily for 72 hours after completing the 3-day course. This sequence was repeated with 100mg SR-DHEA. Adverse outcomes were monitored including pulmonary function testing and asthma control test scores. To assess PD, TopMD software was utilized to characterize molecular phenotypes. Results In this pilot study, SR-DHEA was well-tolerated at both doses with no adverse effects attributed to SR-DHEA. DHEA-S concentrations reach steady-state by 24 hours. With 100mg SR-DHEA treatment, the maximum change of post-bronchodilator FEV1% was significantly improved from baseline (baseline median change: 10.1(95%CI 6.12-14.14) vs. 100mg dose: 18.1(95%CI 10.3-25.7); p = 0.026) and from the 50mg dose (11.1 (95%CI 7.1-15.1); p = 0.008); FEF 25-75% also improved from baseline with the 100mg dose (p = 0.017). Analysis of pathway activation after DHEA administrations revealed downregulation of IL4R and IL13RA1 with suppression increasing at the 100mg dose relative to the 50mg dose (Figure1). Conclusions The 50mg dose of DHEA is sufficient to achieve and sustain elevated DHEA-S levels in adults with severe asthma, however only the 100mg dose significantly improves post-bronchodilator FEV1. Further, molecular phenotyping analysis found increased suppression of a key Th2 inflammatory pathway that was more robust at the 100mg dose. Based on these results, future studies assessing lung function changes should utilize the 100mg dose of SR-DHEA. Further analysis is needed regarding cytokine expression and determining if long-term use of SR-DHEA leads to long-term clinical improvement in patients with asthma. This abstract is funded by: NHLBI