Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience

Reaching target exposure of busulfan-based conditioning prior to hematopoietic stem cell transplantation is vital for favorable therapy outcomes. Yet, a wide inter-patient and inter-occasion variability in busulfan exposure has been reported, especially in children. We aimed to identify factors associated with the variability of busulfan pharmacokinetics in 124 consecutive patients transplanted at the University Children’s Hospital Zurich between October 2010 and February 2020. Clinical data and busulfan plasma levels after twice-daily intravenous administration were analyzed retrospectively by population pharmacokinetic modeling. The volume of distribution correlated with total body water. The elimination rate constant followed an age-dependent maturation function, as previously suggested, and correlated with the levels of serum albumin. Acute lymphoblastic leukemia reduced busulfan clearance by 20%. Clearance significantly decreased by 17% on average from the start to the third day of busulfan administration, in agreement with other studies. An average reduction of 31% was found in patients with hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease. In conclusion, we demonstrate that in addition to known factors, underlying disease and serum albumin significantly impact busulfan pharmacokinetics in pediatric patients; yet, substantial unexplained variability in some patients remained. Thus, we consider repeated pharmacokinetic assessment essential to achieve the desired target exposure in twice-daily busulfan administration

Immunocompromised Host Pneumonia: Definitions and Diagnostic Criteria: An Official American Thoracic Society Workshop Report

Pneumonia imposes a significant clinical burden on people with immunocompromising conditions. Millions of individuals live with compromised immunity because of cytotoxic cancer treatments, biological therapies, organ transplants, inherited and acquired immunodeficiencies, and other immune disorders. Despite broad awareness among clinicians that these patients are at increased risk for developing infectious pneumonia, immunocompromised people are often excluded from pneumonia clinical guidelines and treatment trials. The absence of a widely accepted definition for immunocompromised host pneumonia is a significant knowledge gap that hampers consistent clinical care and research for infectious pneumonia in these vulnerable populations. To address this gap, the American Thoracic Society convened a workshop whose participants had expertise in pulmonary disease, infectious diseases, immunology, genetics, and laboratory medicine, with the goal of defining the entity of immunocompromised host pneumonia and its diagnostic criteria

Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease

Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD

Abstract 316: Effect of schweinfurthins on malignant plasma cells

Abstract Multiple myeloma (MM), a bone marrow neoplasm is currently incurable and effective alternative therapies are needed. Schweinfurthin-3114 (S-3114) purified from a plant extract, inhibits growth of established MM cell lines. The mechanism(s) for this effect are not fully characterized. To advance understanding, MM cell lines RPMI-8226 and MM.1s were incubated with increasing concentrations of S-3114 for up to 48 hours. S-3114 decreased cell viability (trypan blue assay) and mitochondrial activity (MTT assay) in a concentration and time-dependent manner (p≤0.05). RPMI-8226 cells were more sensitive (EC50 2.36 nM) than MM.1s (EC50 11.1 nM) at 48 hours. Flow cytometry analyses revealed increased apoptosis in a concentration and time-dependent manner in both cell lines (64.0% in RPMI-8226 with 20 nM S-3114; 86.3% in MM.1s with 270 nM S-3114, both at 48 hours). S-3114 also induced cell cycle arrest at G2/M. In RPMI-8226, the percent of cells arrested in G2/M increased from 45.9 to 66.1 with 3.5 nM S-3114 at 24 and 48 hours, respectively. In RPMI-8226, 20 nM S-3114 for 24 and 48 hours caused a 100% G2/M arrest. In both cell lines, S-3114 reduced protein kinase B (Akt) activation (Western blot) in a concentration and time-dependent manner. In MM.1s the apoptotic extrinsic pathway (caspase 8), and not the intrinsic pathway (caspase 9), is highly involved. In fact, S-3114 (20 nM for 48 hours, and 270 nM for 24 and 48 hours) caused a major cleavage for both 43 and 18 KDa caspase 8 fragments. Also cleaved Poly ADP-Ribose Polymerase 1 (PARP-1) increased at S-3114 concentrations of 20 and 270 nM at 24 and 48 hours. S-3114 influence on Golgi-mediated secretion was evaluated by measuring the soluble chemokine Macrophage Inflammatory Protein-1 alpha (MIP-1α), which is secreted by the Golgi and it is involved in the progression of MM disease. S-3114 treatment for 48 hours stimulated the MIP-1α negative cell line (RPMI-8226) to significantly increase MIP-1α RNA levels and to secrete MIP-1α at low concentrations. On the contrary, despite that prolonged S-3114 treatment significantly increased MIP-1α RNA levels, its secretion is decreased in the MIP-1α positive cell line (MM.1s). These in vitro studies demonstrate that S-3114 impairs the Phosphoinositide 3-Kinases (PI3K)/Akt signaling pathway resulting in cell death and/or cell cycle arrest. Data also shows an increased gene expression of the pro-survival MIP-1α by S-3114. Our ongoing studies are focused on schweinfurthin effects on MIP-1 α and Golgi secretion. We postulate that the cytotoxic impact of S-3114 requires disruption of MIP-1α signaling to regulate cell cycle, survival, and impairment of Golgi architecture and secretion in malignant plasma cells. In aggregate, these results reveal mechanism(s) for S-3114 effects and support further work advancing S-3114 as a novel therapy for MM. Citation Format: Barbara Manfredi, Raymond J. Hohl. Effect of schweinfurthins on malignant plasma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 316.</jats:p