Article collection: Women’s health and sex differences in ADME research

Clinical Drug development Journal articles Toxicology

Women remain underrepresented in clinical trials, leading to gaps in understanding how they respond to treatments. This article collection from Expert Opinion On Drug Metabolism & Toxicology  highlights the importance of ADME research in women’s health, exploring sex and gender influences on pharmacokinetics, metabolism and toxicology. Featuring contributions from leading experts, the collection aims to advance inclusive drug development, improve therapeutic outcomes and address critical disparities in women’s healthcare. Topics include drug interactions in female-specific diseases, pregnancy-related pharmacokinetics and metabolic differences in drug processing. Below, we have highlighted several key articles from the collection.

Pharmacokinetic evaluation of fezolinetant for the treatment of vasomotor symptoms caused by menopause

Fezolinetant has shown efficacy in reducing the frequency and severity of VMS with a positive impact on sleep- and health-related QoL and acceptable safety and tolerability profile. Given the limited availability of effective non-hormonal options for VMS, fezolinetant could potentially represent a game-changer for care of menopausal women, especially when relative or absolute contraindications to MHT use are present. Further studies to gain more information about the safety profile and potential extra-VMS benefits or disadvantages are warranted in real-life clinical practice.

Article highlights:

  • Vasomotor symptoms (VMS), including hot flashes and night sweats, are very common, being reported by up to 80% of menopausal women, with significant variations in terms of frequency, severity, and impact on the quality of life (QoL).

  • Menopausal hormone therapy (MHT), namely, estrogen alone or in combination with progestogens in women with an intact uterus, are the most effective treatment for VMS.

  • Fezolinetant is a novel oral non-hormonal drug recently approved for the treatment of moderate–severe VMS acting as an antagonist of neurokinin 3 receptor (NK3R), the main target of neurokinin B (a tachykinin over-expressed by kisspeptin/neurokinin B/dynorphin [KNDy] neurons after menopausal hypoestrogenism), involved in the modulation of the thermoregulatory hypothalamic center.

  • Fezolinetant has shown efficacy in reducing the frequency and severity of VMS with a positive impact on sleep- and health-related QoL and acceptable safety and tolerability profile.

  • Further studies are warrented in real-life practice to gain more information about the safety profile and potential extra-VMS benefits or disadvantages of fezolinetant in postmenopausal women.

Read the full Drug Evaluation

Transporters and drug secretion into human breast milk

Although clinical data show that membrane transporters mediate the transfer of multiple drugs into breast milk, our ability to predict milk concentrations for these drugs is limited. Improving our understanding of the transporter biology and pharmacology in the mammary gland is crucial for developing models to predict drug concentrations in human milk, which will support clinicians and lactating individuals in making rational decisions to balance the benefits of breastfeeding and the risks of drug exposure to infants.

Article highlights:

  • Traditional models for predicting milk concentrations of drugs rely on the free drug hypothesis and the assumption that most drugs passively diffuse into milk; however, this model falls short of predicting milk concentrations for drugs with active transfer into milk.

  • Drugs and nutrients may be transferred to milk via passive diffusion, active transport, lipid co-transport, transcytosis, exocytosis, or paracellular transport depending on their physiochemical properties and specific interaction with transport proteins in the mammary epithelial cells.

  • Many ATP-binding cassette (ABC) and solute carrier (SLC) transporters have been identified in the human mammary epithelial gland and could actively influence the concentrations of xenobiotics at the blood-milk barrier.

  • While the impact of the breast cancer resistance protein (BCRP) has been demonstrated, the localization, function, and drug interaction potential of many transporters have yet to be fully characterized in human mammary epithelial cells.

  • A comprehensive and quantitative understanding of transporters in mammary epithelial cells could help predict active milk drug transfer as well as risk of drug-nutrient interaction at the blood-milk interface.

Read the full Review

The oral GnRH antagonists, a new class of drugs in gynecology: from pharmacokinetics to possible clinical applications

The clinical trials examined demonstrated significant efficacy in reducing heavy menstrual bleeding in women with fibroids and pelvic pain in women with endometriosis, with more than 70% of patients achieving primary endpoints. The use of add-back therapy minimized bone mass density loss, ensuring long-term safety. Adverse events were dose-dependent but generally well tolerated. In our opinion, the strength of oral GnRH antagonists lies in their pharmacological properties. Oral administration increases convenience, allows adjustable dosing and ensures a dose-dependent effect. These drugs provide an immediate antagonistic effect without the flare-up phenomenon. Furthermore, they are expected to act on ectopic endometrial and smooth muscle cell receptors, potentially providing additional anti-proliferative effects. However, further research is needed: long term clinical trials must compare them with existing treatments.

Article highlights:

  • Three types of oral GnRH antagonist are available: elagolix, relugolix, linzagolix.

  • They have four peculiarities: oral administration, rapid reversibility of hormonal suppression, immediate suppression, dose-dependent effect.

  • Approved for the treatment of heavy menstrual bleeding associated with uterine fibroids and endometriosis related pelvic pain in women of reproductive age.

  • Favorable safety profile when used at low dosage or for short duration (up to 6 months).

  • The addition of an add back hormonal therapy ensures long-term administration while maintaining efficacy and safety.

  • Further comparative studies with other available drugs are mandatory to confirm their effectiveness.

Read the full Review

Optimizing drug therapy during pregnancy: a spotlight on population pharmacokinetic modeling

Covariate identification can lead to improved mechanistic understanding of drug disposition and establishment of improved dosing regimens during pregnancy. Insufficient data across trimesters may limit the ability of PopPK models to capture time-varying gestational effects.

Article highlights:

  • Population pharmacokinetic modeling enables optimization of drug dosing regimens during pregnancy by accounting for changes in patient physiology and quantifying inter-individual variability in drug exposure.

  • Identification of clinically relevant covariates, such as maternal body weight and gestational age, through population pharmacokinetic models can guide dose individualization and improve therapeutic outcomes among pregnant women.

  • Significant gaps in knowledge regarding mechanistic factors explaining pregnancy associated variability remain.

Read the full Review

Pharmacokinetics and pharmacodynamics of angiogenesis inhibitors used to treat cervical cancer: current and future

Bevacizumab is currently the primary antiangiogenic agent used alongside chemotherapy and has become the standard of care for advanced cervical cancer. However, there are still uncertainties regarding the molecular mechanisms and associations in cervical cancer that could help in optimizing the use of Bevacizumab. Factors such as cost, toxicity, and methodological issues in the GOG-240 trial must be considered.

Article highlights:

  • Despite recent progress, advanced cervical cancer still has a poor prognosis.

  • In 2014, adding the anti-angiogenic bevacizumab to doublet chemotherapy improved survival rates.

  • Pembrolizumab or atezolizumab with combined chemotherapy/bevacizumab have further increased survival.

  • Currently, there is a lack of clinical studies aimed at optimizing the use of bevacizumab in advanced cervical cancer.

  • No new anti-angiogenic drugs are in advanced stages of development.

Read the full Review

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