SAT-LB6 First Human Trial of an Oral Native Testosterone Shows Physiological Levels of Testosterone and Dht in Both Fasted and Fed State in Hypogonadal Men

Introduction: The prevalence of male hypogonadism is estimated to be 6% in the USA (1). Current therapies have limited acceptability: gels can be messy and risk inadvertent dosing of others; injections are painful; and oral testosterone undecanoate (TU) delivers variable testosterone levels, requires concurrent ingestion of a fatty meal and may produce supraphysiological dihydrotestosterone (DHT) levels. We present the first human trial of an oral native testosterone preparation formulated to deliver physiological levels of testosterone irrespective of food intake. Aim: To compare the pharmacokinetics of DITEST (Diurnal Ltd Cardiff, UK) to an oil based oral TU formulation (Andriol Testocaps MSD, UK) and explore the effect of food on DITEST bioavailability. Methods: Single centre, phase 1b study of DITEST in 25 adult males with hypogonadism, one subject withdrawn after single period and only included in safety analysis (Clinicaltrials.gov: NCT02966652). Part 1 compared the pharmacokinetics of 80mg TU with 120mg DITEST after a high fat meal. Part 2 the pharmacokinetics of 200mg of DITEST administered in either fed or fasted states. Results are baseline adjusted. Results: DITEST showed a testosterone dose response between 120mg and 200mg with C(max) 550 (19.1) and 877 (30.4) ng/dl (nmol/l) and AUC(0-10h) 59.5 and 88.6 h*nmol/L. DITEST 200mg gave an equivalent C(max) and AUC(0-10h) to TU 80mg: C(max) 877 (30.4) vs 906 (31.4) ng/dl (nmol/l) and AUC(0-10h) 88.6 vs 102 h*nmol/L. Fed and fasted DITEST had similar pharmacokinetics: C(max) 764 (26.5) vs 877 (30.4) ng/dl (nmol/L), AUC(0-10h) 87.0 vs 88.6. DITEST resulted in lower levels of DHT than TU: C(max) 84 (2.9), 131 (4.5) & 194 (6.7) ng/dl (nmol/l); AUC(0-10h) 11.0, 16.7 & 36.3 h*nmol/L for DITEST 120mg, 200mg & 80mg TU, respectively. There was one serious adverse event (urinary retention) in the study during TU dosing. There were no emerging safety concerns, and adverse event frequency and severity was similar between the two treatments. Discussion: These results demonstrate that 200mg DITEST provides similar testosterone exposure with more physiological DHT exposure than 80mg TU given with a high fat meal. Administration of DITEST in fed and fasted states provides similar testosterone and DHT exposure. Compared to published literature on a self-emulsifying formulation of TU at 200mg, DITEST at 200mg provides a similar testosterone C(max) and no requirement for a fatty meal (2). Conclusion: DITEST is an oral native testosterone formulation with anticipated advantages over current oral therapy of dosing without food and a lower risk of supraphysiological DHT levels. References: 1. Basaria S. Male hypogonadism. Lancet 2014; 383:1250-1263. 2. Yin AY, et al., J Androl 2012; 33:190-201.