Recruitment of pregnant and breastfeeding women in pharmacokinetic studies: strategies, opportunities, barriers, and recommendations.

Pregnant and breastfeeding women are often under-represented in clinical research, including pharmacokinetic studies, due to ethical and logistical challenges. This paper examines strategies to improve the recruitment and retention of this demographic in pharmacokinetic research, drawing on experiences from five studies conducted at the Infectious Diseases Institute, Makerere University, Uganda. Key strategies implemented include Community Advisory Board meetings, the involvement of Peer Mothers as Co-Investigators, established recruitment sites, the use of safety protocols, and the utilization of diverse communication platforms, including social media and stakeholder meetings. Despite these efforts, substantial barriers, such as scheduling conflicts and frequent staff turnover at recruitment sites, continue to threaten progress. The paper recommends flexible scheduling, strengthening public engagement, and transparent demonstration of adherence to ethical principles; justice, non-maleficence, respect, and beneficence to ensure the safety and inclusivity of pregnant and breastfeeding women. The inclusion of this population in pharmacokinetic studies is essential for providing evidence-based care that meets their unique health needs.

Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs.

Pharmacokinetic studies are important for understanding drug disposition in the human body. However, pregnant and lactating women are often excluded from primary pharmacokinetic studies and as such there is often limited dosing information regarding drug use in pregnant and/or lactating women. The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration-time curve of rifampicin in maternal plasma, breastmilk and infant plasma. Performing this interim analysis enabled us to substantiate whether prior assumptions we made on several study design issues including patient sample size and pharmacokinetic sampling times held and whether we needed to amend our protocol or not. We enrolled lactating mothers on treatment for tuberculosis with their breastfeeding infants (below 12 months of age), performed intensive pharmacokinetic sampling (0-24 h post-dose) on plasma samples from both the mother, infant(s) and breastmilk samples from the mother on two separate occasions (once during the initiation phase and another during the continuation phase of tuberculosis treatment). The initial study design, including sampling times, was informed by a stochastic simulation and estimation exercise, with very limited prior breastmilk data. An interim analysis after recruiting 6 mother-infant pairs ascertained that our initial assumptions were ideal for achieving our study objectives and no amendments to the sampling times were necessary. Initial data from 6 mother-infant pairs show that rifampicin penetrates breastmilk with an approximate milk-to-plasma ratio of 0.169 and 0.189 on two separate visits. However, it was undetectable in most infants.

-Pharmacokinetics of antimalarial drugs used to treat uncomplicated malaria in breastfeeding mother-infant pairs: An observational pharmacokinetic study.

Background: Data surrounding the exposure of the breastfed infant to drugs and any associated risks are sparse. Drugs usually are transferred to milk in small quantities, and many have been used without obviously noticeable infant toxicity for many years - this lack of a 'safety signal' has further reduced the interest in studying mother-to-infant transfer of the drugs. In sub-Saharan Africa, pregnant women are at risk of  Plasmodium falciparum infection, and one in four women have evidence of placental infection at the time of delivery. Artemisinin-based combination therapies (ACTs), primarily artemether-lumefantrine (AL), are the current first-line treatment for uncomplicated Plasmodium falciparum malaria, with the same dosing recommendations in breastfeeding women as those in the adult population. Dihydroartemisinin-piperaquine (DP) is routinely used as an alternative to AL in Uganda. However, lactation pharmacokinetics (PK) of ACTs are unknown. Pharmacokinetic characterization of anti-malarial transfer to breast milk and breastfed infants is crucial in understanding the potential consequences to the infant, in terms of therapeutic- and prophylactic effects as well as potential toxicity.   Methods: This observational study will enroll 30 mother-infant pairs, and aims to characterize the breastmilk transfer of antimalarial medications (AL and DP) to infants when these ACTs are administered to mothers as part of treatment for uncomplicated malaria. In addition, we will assess the mental health of the breastfeeding mothers enrolled as well as the well-being of their children. PK samples of maternal blood, breastmilk and breastfeeding infant's blood will be obtained at specific times points. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Conclusions: We anticipate that findings from this research will guide to develop a PK model describing lumefantrine and piperaquine disposition and will provide a framework to foster other lactation pharmacokinetic studies in different disease areas.