Demystifying physiologically based pharmacokinetic modelling among non-modelers towards model-informed medicine use in under-served populations.

Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women. To facilitate broader applications of PBPK for these populations, we joined force and organized five hands-on workshops primarily to non-modelers on the principles of PBPK and its potential applications in pediatric and obstetric pharmacology in 2021 and 2022. In this open letter, we report learning objectives and content of such workshops and to highlight the significant value of these educational efforts.

Pharmacokinetic data in pregnancy: A review of available literature data and important considerations in collecting clinical data.

Pregnancy-related physiological changes can alter the absorption, distribution, metabolism and excretion of medicines which may affect the safety and efficacy of the medicines administered in pregnancy. Pharmacokinetic data can thus be instrumental in supporting dose adjustments required in this population. This review considers the availability of published pharmacokinetic data for over 200 medicines of interest for use in pregnancy in the UK, to identify whether sufficient data currently exists, in principle, for any medicine or group of medicines to support dose adjustments to maintain maternal health through pregnancy. Very limited data was found for many of the medicines of interest. Nevertheless, well documented, large changes of exposure for some drugs, where data is available, highlights the urgent need to collect more data of good quality to inform appropriate doses, when needed, in this population. In addition, clinical study methodology can have an impact on the usefulness of the data and key clinical design aspects are highlighted for consideration in future clinical study design.

Assuring Access to Safe Medicines in Pregnancy and Breastfeeding.

Scientists and regulators in Europe and the United States continue to seek methods and strategies to improve knowledge on rational use of medicines for pregnant and breastfeeding populations, an important subset of women's health. Regulatory agencies have made strides toward improvement, but much more is needed. Recognizing the importance of international collaboration, we have begun to consider how to address these important public health issues more globally. The health of the child begins with the health of the mother.

Recent concerns surrounding HRT.

Millions of women are treated with hormone replacement therapy (HRT) for relief of menopausal symptoms, including vasomotor flushes and sweats for which oestrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HRT will help to prevent chronic disease. The preservation of bone mass with continuing oestrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of oestrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrate no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may be a small increased risk of ovarian cancer associated with longer-term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors and pharmaceutical companies. There are difficulties in extrapolating the results from trials using a specific HRT product to advise women on the wide range of other hormone products, doses, combinations and routes of administration. However, in the absence of evidence that other products are safer, the data suggest that for many women the risks associated with long-term use of HRT outweigh the benefits. There are nonhormonal strategies for the prevention and treatment of osteoporosis. HRT is not, and has never been, licensed in the UK for the prevention or treatment of vascular disease, and the data suggesting potential benefit should now be regarded as biased. The absolute incidence of an adverse event is low, and the risk in an individual woman in a single year is very small, but the risks are cumulative over time with long-term use. The risk-benefit balance of each woman needs regular reappraisal with continued use.