Search

ABSTRACT Background Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but [...]

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV‐seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS‐CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure–response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS‐CMVi through Week 24 or Week 14 among letermovir‐treated participants. Evaluated covariates had no impact on exposure–efficacy relationships and letermovir plasma exposure did not affect time of CS‐CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union. [ABSTRACT FROM AUTHOR]

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem‐cell transplant (HSCT) recipients. In vitro, letermovir is a time‐dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug–drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor. [ABSTRACT FROM AUTHOR]

Understanding and applying context specificity to intracellular signaling is crucial to not only the design of therapeutic interventions for a specific disease, but in the prediction of susceptible patient populations. Tissue specificity arises due to differential tissue functions, it also varies due to quantitative variations in the molecular players. In cancer, different tissues carry different frequencies of mutations. Although one pathway may be more frequently effected, the impact of cross-talk among other pathways is not well understood. Here, we report an integrated approach to analyzing pathway cross-talk in the context of the genetics of hepatocellular carcinoma. We identify three key pathways using genetic and therapeutic considerations. Interactions among the approximately 25 molecular players are generated using text mining and verified by consideration of phosphoproteomic data. The interactions are then analyzed using logic-based modeling to predict the best pair wise combination of targets that increase cell apoptosis. Hypotheses are tested in vitro. This analysis demonstrates the effective integration of methods that improve our ability to consolidate our current knowledge and increase the effectiveness of therapeutic programs. [ABSTRACT FROM AUTHOR]

G protein-coupled receptor (GPCR) mediation of cardiac excitability is often overlooked in predicting the likelihood that a compound will alter repolarization. While the areas of GPCR signal transduction and electrophysiology are rich in data, experiments combining the two are difficult. In silico modelling facilitates the integration of all relevant data in both areas to explore the hypothesis that critical associations may exist between the different GPCR signalling mechanisms and cardiac excitability and repolarization. An example of this linkage is suggested by the observation that a mutation of the gene encoding HERG, the pore-forming subunit of the rapidly activating delayed rectifier K+ current (I(Kr)), leads to a form of long QT syndrome in which affected individuals are vulnerable to stress-induced arrhythmia following beta-adrenergic stimulation. Using Physiome's In Silico Cell, we constructed a model integrating the signalling mechanisms of second messengers cAMP and protein kinase A with I(Kr) in a cardiac myocyte. We analysed the model to identify the second messengers that most strongly influence I(Kr) behaviour. Our conclusions indicate that the dynamics of regulation are multifactorial, and that Physiome's approach to in silico modelling helps elucidate the subtle control mechanisms at play.