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The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present.
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Antineoplásicos , Neoplasias da Mama , Hidrocarbonetos Aromáticos com Pontes , Docetaxel , Feminino , Humanos , Paclitaxel , TaxoidesRESUMO
Everybody deserves access to evidence-based information to make decisions about their health. However, in many situations, clinical trial eligibility criteria mean that specific data do not exist for certain groups of individuals. These include pregnant and breastfeeding women, children, older people, those with hepatic and renal dysfunction, those with acute severe illness, and those with multiple co-morbidities and interacting medications. Resultantly, there may not be specific drug-dosing information for many patients who are treated in a clinical setting. The ASCPT2024 Dolores Shockley Lecture focused on the equitable access to research with a specific focus on clinical pharmacology studies in pregnancy and breastfeeding. To ensure the safe, effective use of medication in pregnancy and breastfeeding, women should be included in clinical trials and pharmacokinetic studies when a medication is anticipated to be used in women of childbearing potential. Community groups should be involved at all stages of research to maintain transparency and trust. This ensures that local priorities are investigated, that communities understand the findings and are empowered to make evidence-based decisions about their own medication use. Principles informing the design of such studies in pregnancy and lactation are in existence. Mathematical techniques such as physiologically-based pharmacokinetic modeling and stochastic simulation and estimation can enhance study design, and population pharmacokinetic modeling be used to understand variability within and between individuals. Data should be made findable, accessible, interoperable, and reusable (FAIR). Information (and where necessary, training) regarding the use of these approaches should be provided to decision-making stakeholders such as ethics committees and regulatory bodies.
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BACKGROUND: Exclusive breastfeeding of infants under 6 months of age is recommended by the World Health Organization. In 2021, over 300 million combined incident cases of malaria, tuberculosis, and neglected tropical diseases (NTDs) were reported, predominantly in low-income countries. For many of the drugs used as first-line treatments for these conditions, there is limited knowledge on infant exposure through breastfeeding with poorly understood consequences. This review summarized available knowledge on mother-to-infant transfer of these drugs to inform future lactation pharmacokinetic studies. METHODOLOGY: A list of first-line drugs was generated from the latest WHO treatment guidelines. Using standard online databases, 2 independent reviewers searched for eligible articles reporting lactation pharmacokinetics studies and extracted information on study design, participant characteristics, and the mathematical approach used for parameter estimation. A third reviewer settled any disagreements between the 2 reviewers. All studies were scored against the standardized "ClinPK" checklist for conformity to best practices for reporting clinical pharmacokinetic studies. Simple proportions were used to summarize different study characteristics. FINDINGS: The most remarkable finding was the scarcity of lactation pharmacokinetic data. Only 15 of the 69 drugs we listed had lactation pharmacokinetics fully characterized. Most studies enrolled few mothers, and only one evaluated infant drug concentrations. Up to 66% of the studies used non-compartmental analysis to estimate pharmacokinetic parameters rather than model-based compartmental analysis. Unlike non-compartmental approaches, model-based compartmental analysis provides for dynamic characterization of individual plasma and breast milk concentration-time profiles and adequately characterizes variability within and between individuals, using sparsely sampled data. The "ClinPK" checklist inadequately appraised the studies with variability in the number of relevant criteria across different studies. CONCLUSIONS/SIGNIFICANCE: A consensus is required on best practices for conducting and reporting lactation pharmacokinetic studies, especially in neglected diseases such as malaria, tuberculosis, and NTDs, to optimize treatment of mother-infant pairs.
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Malária , Tuberculose , Feminino , Lactente , Humanos , Leite Humano , Doenças Negligenciadas/tratamento farmacológico , Aleitamento Materno , Lactação , Tuberculose/tratamento farmacológicoRESUMO
Paclitaxel/platinum chemotherapy, the backbone of standard first-line treatment of advanced non-small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure-driven early tumor response for improved prediction of overall survival (OS) is clinically not established. We developed a Weibull time-to-event model to predict OS, leveraging data from 365 patients receiving paclitaxel/platinum combination chemotherapy once every three weeks for ≤six cycles. A developed tumor growth inhibition model, combining linear tumor growth and first-order paclitaxel area under the concentration-time curve-induced tumor decay, was used to derive individual RS8. The median model-derived RS8 in all patients was a 20.0% tumor size reduction (range from -78% to +15%). Whereas baseline carcinoembryonic antigen, cytokeratin fragments, and thyroid stimulating hormone levels were not significantly associated with OS in a subset of 221 patients, and lactate dehydrogenase, interleukin-6 and neutrophil-to-lymphocyte ratio levels were significant only in univariate analyses (p value < 0.05); C-reactive protein (CRP) in combination with RS8 most significantly affected OS (p value < 0.01). Compared to the median population OS of 11.3 months, OS was 128% longer at the 5th percentile levels of both covariates and 60% shorter at their 95th percentiles levels. The combined paclitaxel exposure-driven RS8 and baseline blood CRP concentrations enables early individual prognostic predictions for different paclitaxel dosing regimens, forming the basis for treatment decision and optimizing paclitaxel/platinum-based advanced NSCLC chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Paclitaxel , Neoplasias Pulmonares/patologia , Prognóstico , Platina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Background: Pre-exposure prophylaxis (PrEP) is an important intervention for reducing the risk of HIV transmission among high-risk populations such as female sex workers in Africa, where HIV prevalence remains high. We aimed to assess the use of PrEP among female sex workers in Gulu, Uganda. Methods: In this community-based cross-sectional study, we included HIV-negative female sex workers purposely selected from hotspots within Gulu city, Uganda between February and March 2023. A semi-structured questionnaire was administered to collect data on sociodemographic characteristics, reproductive data, sexual practices, and self-reported PrEP use in the past 3 months. Symptoms of depression were screened using Patient Health Questionnaire-2 tool. Predictors of PrEP use was determined using modified Poisson regression analysis model. p < 0.05 was considered statistically significant. Results: We enrolled 273 female sex workers with a median age of 27 (interquartile range: 24-32) years. Overall, 181 (66.3%) participants used PrEP. PrEP use was associated with; regular source of income beside sex work [adjusted prevalence ratio (aPR): 3.7, 95% confidence interval (CI): 2.11-6.35, p < 0.001], being in a polygamous marriage (aPR: 6.9, 95% CI: 1.32-35.77, p = 0.022), practicing sex work in both rural and urban areas (aPR: 2.5, 95% CI: 1.49-4.35, p < 0.001), having symptoms of depression (aPR: 3.3, 95% CI: 1.43-7.74, p = 0.005), and use of postexposure prophylaxis (PEP) in the past 12 months (aPR: 0.31, 95% CI: 0.17-0.59, p < 0.001). Conclusion: Almost two in three of the female sex workers in Gulu city were currently using PrEP. Previous use of PEP was associated with lower use of PrEP. These findings suggest the need for targeted interventions to increase PrEP uptake and decrease HIV acquisition in this high-risk population among female sex workers, especially those with low income and limited access to healthcare.
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In oncology, longitudinal biomarkers reflecting the patient's status and disease evolution can offer reliable predictions of the patient's response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions.
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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.
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Background: Globally, more than half of women take medicines whilst breastfeeding. Data concerning the exposure of the breastfed infant to drugs and any related risks are sparce. Lactation studies are only rarely performed close to licensing for medicines anticipated to be widely used in women of childbearing age. Medicines taken by breastfeeding mothers on tuberculosis (TB) treatment can be transferred to the breastfed infant. Potential effects of anti-tuberculosis medicines on nursing infants are not well understood. Similarly, women face mental health challenges while taking medications, including postpartum depression, hence the need to assess the psychological behavior of a breastfeeding woman. Potential risks are the development of adverse drug effects in the breastfed infant and selection for resistance, whereas potential benefits might include exposure to potentially prophylactic concentrations of the drug. Pharmacokinetic studies are therefore necessary to understand this situation fully. Methods: This study will enroll 20 mothers receiving first-line anti-tuberculosis medicines, together with their breastfed infants, with the aim of characterizing the breastmilk transfer of the medicines from the mother to the infants. Samples of maternal blood, breastmilk, and breastfeeding infant's blood will be obtained at specific time points for bioanalysis of drug concentrations. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Additionally, the study will assess the psychological status of breastfeeding women and the well-being of their infants. Maternal depression is linked to long-term negative consequences for the infant's physiological regulation, poor growth-promoting setting for the infants, and inappropriate interactive conduct, characterized by low compassion, constrained range of emotional expression, and varying provision of the infant's budding engagement. Conclusions: This study will provide the first systematic characterization of mother-to-infant transfer of first-line anti-tuberculosis medicines through breast milk. A mathematical pharmacokinetics model characterizing plasma-to-breastmilk transfer of rifampicin, isoniazid, ethambutol, and pyrazinamide will be developed and used to characterize infant exposure through breast milk. Our findings will contribute towards treatment optimization in breastfeeding and provide a framework to foster other lactation pharmacokinetic studies.