Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia.

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.

The therapeutic potential of resolvins in pulmonary diseases.

Uncontrolled inflammation leads to nonspecific destruction and remodeling of tissues and can contribute to many human pathologies, including pulmonary diseases. Stimulation of inflammatory resolution is considered an important process that protects against the progression of chronic inflammatory diseases. Resolvins generated from essential omega-3 polyunsaturated fatty acids have been demonstrated to be signaling molecules in inflammation with important pro-resolving and anti-inflammatory capabilities. By binding to specific receptors, resolvins can modulate inflammatory processes such as neutrophil migration, macrophage phagocytosis and the presence of pro-inflammatory mediators to reduce inflammatory pathologies. The discovery of these pro-resolving mediators has led to a shift in drug research from suppressing pro-inflammatory molecules to investigating compounds that promote resolution to treat inflammation. The exploration of inflammatory resolution also provided the opportunity to further understand the pathophysiology of pulmonary diseases. Alterations of resolution are now linked to both the development and exacerbation of diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, cancer and COVID-19. These findings have resulted in the rise of novel design and testing of innovative resolution-based therapeutics to treat diseases. Hence, this paper reviews the generation and mechanistic actions of resolvins and investigates their role and therapeutic potential in several pulmonary diseases that may benefit from resolution-based pharmaceuticals.

Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach.

BACKGROUND AND OBJECTIVE: Information on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to differences in milk production. Consequently, little is known about the variability of chemotherapy distribution to breast milk and the effect of milk production on the distribution of chemotherapy to breast milk. Our aim was to predict chemotherapy distribution to breast milk in a more realistic breastfeeding population and evaluate the effect of discarding breast milk on the potential chemotherapy exposure in infants. METHODS: We developed a population pharmacokinetic model that described the breast milk production and the chemotherapy distribution to breast milk of a non-breastfeeding population, linked it to plasma pharmacokinetics, and extrapolated this to a breastfeeding population. RESULTS: We found that cumulative relative infant doses (RID) were higher than 10% for cyclophosphamide and doxorubicin and approximately 1% for paclitaxel. Simulations allowed us to predict the cumulative RID and its variability in the population for patients with different milk productions and the amount of breast milk that has to be discarded to reach cumulative RIDs below 1%, 0.1%, and 0.01%. Discarding 1-2, 3-6, and 0-1 days of breast milk (depending on the milk production of the patient) resulted in cumulative RID below 1% for cyclophosphamide, doxorubicin, and paclitaxel, respectively. CONCLUSION: Our results may help clinicians to derive the optimal breast milk discarding strategy for an individual patient that wants to breastfeed during chemotherapy and minimize chemotherapy exposure in their infants.