Abstract
BackgroundThere is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse.MethodWe summarize current thinking and provide clinical trial considerations for a consistent approach to contraception for males exposed to genotoxic and/or teratogenic compounds or to compounds of unknown teratogenicity, and for collection of pregnancy data from their female partners.ResultsWhere toxicity testing demonstrates genotoxic potential, condom use is required during exposure and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) to avoid conception.For non-genotoxic small molecules and immunoglobulins with unknown teratogenic potential or without a no observed adverse effect level (NOAEL) from embryo-fetal development (EFD) studies and no minimal anticipated biological effect level (MABEL), condom use is recommended for males with pregnant partner/female partner of childbearing potential. For teratogenic small molecules with estimated seminal fluid concentration and a margin between projected maternal area under the curve (AUC) and NOAEL AUC from EFD studies of ≥300 (≥100 for immunoglobulins) or in the absence of a NOAEL with a margin between MABEL plasma concentration and maternal Cmax of ≥300 (≥10 for immunoglobulins), condom use is not required. However, condom use is required for margins below the thresholds previously indicated. For small molecules with available seminal fluid concentrations, condom use is required if margins are <100 instead of <300. Condom use should continue for as long as the projected margin is at or above the defined thresholds.Pregnancy data should be proactively collected if pregnancy occurs during the condom use period required for males exposed to first-in-class molecules or to molecules with a target/class shown to be teratogenic, embryotoxic or fetotoxic in human or preclinical experiments.ConclusionThese recommendations, based on a precaution principle, provide a consistent approach for minimizing the risk of embryo-fetal exposure to potentially harmful drugs during pregnancy of female partners of males in clinical trials. Proactive targeted collection of pregnancy information from female partners should help determine the teratogenic potential of a drug and minimize background noise and ethical/logistical issues.
Highlights
There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse
Impact of preclinical findings on protocol eligibility criteria for males and on collection of pregnancy information from their female partners Genotoxic compounds: Condom use for avoiding conception A potential risk for birth defects due to DNA damage in the germ cells of the father is conceivable
Teratogenic compounds: Condom use for avoiding vaginal dose The potential risk to progeny from teratogenic compound exposure via the vaginal dose is considered to be low since the transfer of a drug via seminal fluid to the embryo-fetus is minor
Summary
There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse. Genotoxic molecules may cause DNA damage or impairment of chromosome replication, which may be passed on to progeny at conception when damage occurs to the genetic material of germ cells. Depending on the type (e.g., gene mutations, chromosomal aberrations, chromosomal misdistributions) and location of the damage, genetic alterations may lead to embryo-fetal death, birth defects or hereditary defects. Teratogenic molecules may affect embryogenesis and fetal development, leading to birth defects. Regulatory guidance and instructions in local package inserts address restriction of the use of genotoxic and teratogenic compounds in women of childbearing potential (WOCBP) and pregnant women. Fathering a child should be prevented during and for an appropriate period of time after dosing with genotoxic molecules
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
