An open‐label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners

Abstract

Aims Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner. Methods An open‐label, single‐dose study in 12 healthy men was conducted over a 106‐day period. Subjects received a single subcutaneous dose of 60‐mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded. Results Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax) was 6170 (2070) ng ml–1 (serum) and 100 (81.9) ng ml–1 (seminal fluid). The median time to Cmax (tmax) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration–time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast) was 333 000 (122 000) day•ng ml–1 (serum) and 5220 (4880) day•ng ml–1 (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived ‘no effect level’ for denosumab. Conclusions These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

RANKL regulates male reproductive function

“…However, prolonged treatment with OPG for five weeks had no effect on testicular weight or sperm counts. The lack of effect after five weeks of treatment may be explained by autoantibodies, exhaustion, or compensation and is in line with long-term Denosumab toxicology studies in monkeys 32 , 36 , while the observed increase in sperm production after two weeks of treatment could be due to decreased apoptosis rather than increased germ cell proliferation. TRAIL, a potent apoptosis-inducer in the testis is effectively blocked by OPG 33 , 34 , and TRAIL inhibition could in theory lead to less apoptosis and thus a faster increase in sperm counts 33 , 35 .…”

“…Importantly, the testicular expression pattern of RANKL signaling is overall conserved between mice and humans. Ex vivo cultures of human testicular tissue allowed us to compare the effects of OPG and Denosumab treatment, used in concentrations lower than actually measured in seminal fluid following subcutaneous injection 36 , on human germ cell apoptosis and proliferation. The comparable anti-apoptotic effects on human germ cells and suppression of RANKL released into the media of OPG and Denosumab treatment show that the effect is mediated through RANKL signaling rather than by TRAIL.…”

“…Safety is a concern when applying new drugs related to reproductive function and Denosumab needs to be carefully evaluated because it is a known teratogen. After the initial approval of the drug FDA requested measurements of Denosumab levels in the seminal fluid and these studies showed that transfer to the woman or the fetus was not likely to take place 36 . Moreover, subcutaneous Denosumab (Prolia ® ) is used clinically worldwide to treat osteoporosis and considered a safe treatment option with frequent mild and a few rare serious side-effects such as osteonecrosis of the jaw and atypical femoral fractures 42 .…”

Clinical trial considerations on male contraception and collection of pregnancy information from female partner: update

“…Monoclonal antibodies (mAbs): For mAbs, the calculation of the vaginal dose assumes a seminal concentration of 1 % of the plasma concentration because this is the ratio commonly reported for IgGs [ 16 – 18 ]. In a recent publication on an IgG2, a 2 % ratio for seminal fluid/plasma concentration was measured [ 19 ]. The extent of vaginal absorption is assumed as 10 % given the limited information available [ 20 , 21 ].…”

Effect of a single-dose denosumab on semen quality in infertile men (the FITMI study): study protocol for a randomized controlled trial

“…As denosumab has a teratogenic effect, pharmacokinetic studies in both monkeys and healthy men were performed before approval of the drug as a treatment for osteoporosis in men. These studies showed that denosumab concentration in semen does not pose a risk to the fetus during sexual intercourse with the pregnant woman and therefore is safe to use for the suggested infertility indication as there is no risk of fetal transmission [ 19 , 20 ].…”