A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project

open17siBreastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extrapolation (IVIVE) algorithms and mechanistic insights. Such a non-clinical platform will be developed and thoroughly evaluated by the Innovative Medicines Initiative ConcePTION.openNauwelaerts N.; Deferm N.; Smits A.; Bernardini C.; Lammens B.; Gandia P.; Panchaud A.; Nordeng H.; Bacci M.L.; Forni M.; Ventrella D.; Van Calsteren K.; DeLise A.; Huys I.; Bouisset-Leonard M.; Allegaert K.; Annaert P.Nauwelaerts N.; Deferm N.; Smits A.; Bernardini C.; Lammens B.; Gandia P.; Panchaud A.; Nordeng H.; Bacci M.L.; Forni M.; Ventrella D.; Van Calsteren K.; DeLise A.; Huys I.; Bouisset-Leonard M.; Allegaert K.; Annaert P

A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBP

Developmental toxicity studies of lumefantrine and artemether in rats and rabbits

The combination of artemether plus lumefantrine (AL) is a type of artemisinin-based combination therapy (ACT) recommended since 2001 by the World Health Organization (WHO) for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin and artemether in animals. . Before recommending ACTs for use in the first trimester, the WHO has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo-fetal development studies of artemether alone, lumefantrine alone and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no effect levels (dNOELs) for lumefantrine were 500 mg/kg/day in rats and 1000 mg/kg/day in rabbits and the calculated safety margins based on human equivalent dose (HED) and plasma Cmax and AUC values were in the range of 3-fold to 12-fold. The dNOELs for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. No teratogenicity was observed in these studies with either compound. There were no unexpected findings with artemether or AL. The results with lumefantrine indicate that it is not a potent embryotoxin in rats and rabbits. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether-lumefantrine in the first trimester compared to other ACTs

The use of optical imaging to assess the potential for embryo-fetal exposure to an exogenous material after intravaginal administration

The combination of transgenic reporter mice (beta-actin-luc, Taconic) and sensitive optical imaging methodology enables us to quickly measure potential exposure of a developing embryo-fetus after intravaginal exposures to the reporter substrate, D-luciferin. Here we show how the stages of the estrous cycle affect the distribution of imaging agents into the female reproductive tract. Moreover, by crossing transgenic male and wild-type female mice, we produce pregnant female mice with the transgenic imaging reporter gene in a proportion of the offspring only. We clearly demonstrate that the imaging substrate administered intravaginally can rapidly reach the developing embryo-fetus. Transgenic reporter mice provide a unique opportunity to help us better understand the potential mechanism for embryonic/fetal exposure to drugs following intravaginal exposure via seminal fluid or a direct intravaginal delivery system. The drug could cross the cervix and enter the uterine environment, leading to direct embryo-fetal exposure in utero and/or be absorbed into the maternal circulation with subsequent exposure to the embryo-fetus. After intravaginal administration of the D-luciferin substrate (or D-luciferin mixed with a fluorescent dye), the ability of the substrate to enter the uterus was evaluated during different stages of the estrous cycle. Bioluminescence was observed throughout the reproductive tract during diestrus, but not during estrus. D-luciferin was first detected approximately 2-5 minutes after intravaginal administration to female beta-actin-luc mice. Similar results were obtained when a fluorescent probe was administered intravaginally to wild-type female mice. Intravaginal administration of D-luciferin to wild-type female mice that had been mated with male beta-actin-luc mice indicated that the substrate reached the developing embryo-fetus, with bioluminiescence corresponding to transgene expression in the embryo-fetus. D-luciferin substrate rapidly reached the embryo-fetus (within minutes) regardless of the administration route (intravaginal, intraperitoneal, subcutaneous, or intravenous). Vaginal ligation appeared to block at least some direct exposure to the embryo-fetus, but did not prevent the D-luciferin substrate from eventually reaching the embryo-fetus, perhaps as a result of limited systemic uptake from the vagina. In conclusion, intravaginal administration of a bioluminescent or fluorescent substrate resulted in its rapid distribution (within minutes) to the developing embryo-fetus, which was not prevented by vaginal ligation. Additional work will be necessary to form the basis for a reliable assessment of the human risk for male-mediated teratogenicity

Women’s representation at an academic dermatology conference: trending upwards, but not equal yet

Although women make up a significant portion of the workforce in dermatology, they remain underrepresented in academia. This study investigates the number of male and female symposium speakers at the American Academy of Dermatology annual meetings over a three-year period and compares research productivity and academic rank between the men and women invited to speak. The results demonstrate a steady increase in the representation of female symposium speakers at the conference from 2016 to 2018, although a higher proportion of invited male speakers hold professorships and leadership positions. This upward trend in women's representation may translate to more opportunities for female engagement in academic dermatology. Although women make up over 60% of residents in dermatology, they are not proportionally represented in this conference sample. This imbalance in representation demonstrates that further interventions to increase the representation of female professors and chairs may be necessary

Potential seminal transport of pharmaceuticals to the conceptus

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products assumes a daily dose of 5 mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a risk to the conceptus

A comprehensive review on non-clinical methods to study transfer of medication into breast milk - A contribution from the ConcePTION project.

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extrapolation (IVIVE) algorithms and mechanistic insights. Such a non-clinical platform will be developed and thoroughly evaluated by the Innovative Medicines Initiative ConcePTION