Enclomiphene Citrate Pharmacokinetics (ADME): Absorption, Distribution, Metabolism, and Excretion

How enclomiphene relates to clomiphene

Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis) [1]. FDA notes that the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [1]. The two are related but not interchangeable, and the isomer-specific kinetic studies below gave the mixture and measured each isomer separately [4][5].

Enclomiphene is the more anti-estrogenic, pro-gonadotropic isomer, while zuclomiphene is more estrogenic [6].

In a single-dose study of 24 healthy women, the trans (enclomiphene) isomer reached peak levels earlier than zuclomiphene and was eliminated much faster, and zuclomiphene was still detectable up to a month after treatment [4].

In 9 women with polycystic ovary syndrome given one 50 mg dose of clomiphene citrate, enclomiphene had a mean peak concentration of 15 ng/mL at a mean of 3 hours and an AUC of 65 ng/mL·h over 72 hours, with wide between-patient variation (68 percent coefficient of variation on time to peak). Zuclomiphene in the same study had an AUC of 1,289 ng/mL·h measured over 456 hours [5]. Those AUCs cover different time windows, so they are not a like-for-like comparison.

Absorption: how fast does enclomiphene get into the blood?

Enclomiphene is absorbed rapidly, with peak concentrations about 2 to 3 hours after an oral dose [1]. The Clomid label covers the clomiphene mixture rather than isolated enclomiphene, and it describes clomiphene citrate as readily absorbed after oral use [7].

The most detailed human work in men comes from a randomized, single-blind, two-centre phase 2 study of 48 men with secondary hypogonadism. It measured total testosterone and LH every hour for 24 hours after a first dose and again after six weeks of daily enclomiphene at 6.25, 12.5 or 25 mg, compared with transdermal testosterone gel; testosterone and LH rose with enclomiphene [2].

Distribution: what is known

The clearest distribution data come from single-dose isomer work. In the 9 women with polycystic ovary syndrome, the terminal slope was very flat with a long-tailed residence time, which the authors attributed to the compound's lipophilic nature and potentially extensive distribution [5]. Obesity influenced zuclomiphene kinetics more strongly than enclomiphene kinetics in that study [5]. The Clomid label says zuclomiphene's persistence for longer than a month may suggest stereo-specific enterohepatic recycling or sequestering of that isomer [7].

Metabolism: what happens in the liver

The main metabolite is 4-hydroxy enclomiphene [1].

Excretion and half-life

Enclomiphene is excreted mainly in feces [1]. The quantitative excretion figures come from radiolabeled clomiphene citrate, which cannot separate the isomers: cumulative urinary and fecal excretion averaged about 50 percent of an oral dose after 5 days, with mean urinary excretion of about 8 percent and fecal excretion of about 42 percent, and some labeled material was still present in feces 6 weeks later [7].

Plasma half-life for enclomiphene is about 10 hours [1]. Zuclomiphene behaves very differently: in single-dose studies it was still detectable more than a month after dosing [7], and the 24-woman study found significant plasma concentrations up to 1 month after treatment [4].

Dosing and what happens after stopping

Doses actually studied are 6.25, 12.5 and 25 mg once daily by mouth [2]. Phase 3 protocols used 12.5 mg once daily, with up-titration to 25 mg daily at week 6 if morning testosterone stayed below 300 ng/dL [8].

In a phase 2b study of 12 men, testosterone fell back to pre-treatment values one month after stopping enclomiphene [10].

Approval status and safety

Enclomiphene has no FDA-approved product [1]. In January 2018 EMA's committee recommended refusing marketing authorisation for EnCyzix, citing a venous thromboembolism risk and studies that raised testosterone without showing symptom improvement, based on 4 main studies in 588 patients [3]. In 2022 FDA listed cardiac and thromboembolic events (including pulmonary embolism and deep vein thrombosis in a safety study), raised estradiol, raised PSA and raised hematocrit as concerns from published trials, adverse-event reports and EMA's review, alongside the absence of long-term safety data [1].

The most frequent side effects in the phase 3 and EMA data were headache, hot flushes, nausea and muscle spasm. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo, and nausea by 4 of 112 and 3 of 47 [11]. Blurred vision was among the reasons men stopped treatment [11], and the Clomid label carries a visual-symptom warning for the clomiphene mixture [7].