Challenges with sirolimus experimental data to inform QSP model of post-transplantation cyclophosphamide regimens.

Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

Platelet transfusions in a murine model of neonatal polymicrobial sepsis: Divergent effects on inflammation and mortality.

BACKGROUND: Platelet transfusions (PTxs) are often given to septic preterm neonates at high platelet count thresholds in an attempt to reduce bleeding risk. However, the largest randomized controlled trial (RCT) of neonatal transfusion thresholds found higher mortality and/or major bleeding in infants transfused at higher thresholds. Using a murine model, we investigated the effects of adult PTx on neonatal sepsis-induced mortality, systemic inflammation, and platelet consumption. STUDY DESIGN AND METHODS: Polymicrobial sepsis was induced via intraperitoneal injection of cecal slurry preparations (CS1, 2, 3) into P10 pups. Two hours after infection, pups were transfused with washed adult Green Flourescent Protein (GFP+) platelets or control. Weights, platelet counts, and GFP% were measured before 4 and 24 h post-infection. At 24 h, blood was collected for quantification of plasma cytokines. RESULTS: The CS batches varied in 24 h mortality (11%, 73%, and 30% in CS1, 2, and 3, respectively), due to differences in bacterial composition. PTx had differential effects on sepsis-induced mortality and systemic inflammatory cytokines, increasing both in mice infected with CS1 (low mortality) and decreasing both in mice infected with CS2 and 3. In a mathematical model of platelet kinetics, the consumption of transfused adult platelets was higher than that of endogenous neonatal platelets, regardless of CS batch. DISCUSSION: Our findings support the hypothesis that transfused adult platelets are consumed faster than endogenous neonatal platelets in sepsis and demonstrate that PTx can enhance or attenuate neonatal inflammation and mortality in a model of murine polymicrobial sepsis, depending on the composition of the inoculum and/or the severity of sepsis.