Oral Administration of Enclomiphene Citrate Results in Physiological Total Testosterone Levels in Men with Low or Normal Testosterone: A Pilot Study

Abstract

Background: Clomiphene Citrate may be used off-label to treat men with secondary hypogonadism. More commonly used and approved are the exogenous testosterone products such as gels, patches, and injectables. One drawback may be the high levels of serum testosterone (TT) achieved with exogenous products. A single isomer of Clomiphene citrate, Enclomiphene citrate, is in development and may be useful and gain regulatory approval. An open question is whether men using Enclomiphene citrate will experience high levels of TT. Aims: In our efforts to evaluate Enclomiphene citrate as an oral therapy for normalizing testosterone, we conducted a Phase I pilot clinical study (ZA-002: An Open Label, Fixed Dose, Single Center, Phase I Study to Evaluate the Changes in Total Testosterone with Oral Administration of Enclomiphene Citrate in Healthy Men with Low and Normal Testosterone) to assess the compound's effects on TT. Methods: Sixteen men, mean age 46, with low or normal testosterone levels were enrolled and 13 administered Enclomiphene Citrate drug for two weeks. The pharmacodynamics effects of Enclomiphene citrate on total testosterone (TT) were investigated. The Phase I study also assessed the safety and tolerability of Enclomiphene citrate in middle aged subjects. Results: An increase in TT was observed in males with low baseline levels following 14 days of Enclomiphene citrate. The mean increase in TT ranged from147 ng/dL to 339 ng/dL and results in an increase into the normal range with few excursions above the upper limits. TT increases were greater in men with normal testosterone at baseline. After 14 days of Enclomiphene citrate, mean testosterone levels over a 24-hour sampling period were relatively similar with respect to Cavg. There was a trough in TT 12 hours after administration. TT levels returned to baseline within 28 days of the last dose of Enclomiphene citrate. No clinically meaningful effects on vital signs, laboratory safety tests or ECG results were noted.