Challenge:
To anticipate possible adverse drug reactions, a client requested clarification of the mechanisms which induce and sustain bronchoconstriction in asthma patients
Approach:
Research was conducted in a Respiratory PhysioPD™ Research Platform representing a pulmonary neuromuscular junction, the effects of a methacholine (MCh) challenge, and the impact of inflammation on FEV1 (Forced Expiratory Volume) response to the MCh challenge
Results:
An analysis of the bronchoconstriction mechanisms and simulation of the Platform clarified the role of endogenous acetylcholine in sustaining bronchoconstriction, illustrating the mechanisms by which inflammation worsens the FEV1 response to the MCh challenge
Impact:
The Respiratory PhysioPD Platform research provided a prospective evaluation of bronchoconstriction outcomes for therapies that interact with pulmonary muscarinic biology to help guide rational drug development
Challenge:
The client requested identification of an optimal dose and dosing schedule for a novel oncology antibody therapy with multiple mechanisms
Approach:
An Oncology PhysioPD Platform was used to identify sensitive metabolic pathways in a growth factor-expressing tumor. The impact of dose and schedule variations on sensitive pathways was evaluated using simulated treatment with the antibody therapeutic
Results:
PhysioPD Research identified key drivers of therapeutic response and found patient characteristics (effector : target cell ratio) had greater impact than variations in drug dose and schedule
Impact:
The PhysioPD Research results increased confidence in the clinical trial design and identified potential biomarkers to guide patient inclusion criteria
Challenge:
To identify patient characteristics indicative of therapy responders/non-responders, a client required evaluation of the efficacy and dosing strategies of an interleukin-2 receptor subunit beta (CD122)–biased agonist as a monotherapy and in combination with a programmed cell death protein 1 (PD-1) inhibitor
Approach:
An Immuno-Oncology PhysioPD™ Research Platform and Virtual Patients (VPs) with mechanistic variability that would impact the clinical response to various therapies were used to assess the efficacy of therapies on clinical outcomes.
Results:
PhysioPD Research suggested the CD122 agonist combined with a PD-1 inhibitor showed superior efficacy compared with PD-1 inhibitor monotherapy in PD-1 inhibitor non-responder VPs. Simultaneous dosing of the CD122 agonist and a PD-1 inhibitor may be more efficacious than sequential alternate dosing or preloading with either drug
Impact:
The PhysioPD Platform Research provided a mechanistic-based identification of which patients would have the best response to treatment and support for a drug combination therapy
Challenge:
An FDA review found a perceived inconsistency between reductions in glycated hemoglobin (A1C) and average plasma glucose changes in a clinical trial of a drug with a poorly characterized mechanism of action. A client requested an evaluation of the data and identification of potential reasons for the perceived inconsistency
Approach:
Research utilized a Type 2 Diabetes (T2D) PhysioPD™ Research Platform with Virtual Patients (VPs) consistent with client Phase III trial data to generate hypotheses explaining the observed relationships between A1C and glucose.
Results:
PhysioPD Research found that the selection of clinical trial subjects and sampling times of fasting plasma glucose likely contributed to the perceived mismatch between A1C and glucose. The variability in dietary carbohydrate between clinical trial sites may have impacted the observed response
Impact:
The results of the PhysioPD Research informed the client strategy for planned FDA discussions, and resulted in recommended strategies for future T2D drug trial design
Challenge:
Determining dose for pediatric use of drugs can be problematic due to physiological differences between adults and neonates. A client requested an assessment of the pharmacokinetic/ pharmacodynamic (PK/PD) relationship of ursodiol to select the dosing for pediatric use.
Approach:
A clinical trial using microdosing in newborn infants and the use of accelerator mass spectrometry provided a limited data set with high variability. A PK model and a PhysioPD™ Platform were developed and used to research underlying causes for the variability
Results:
Analysis of the PK model provided key information of the use of AMS data for pediatric PK. PhysioPD™ Research identified and explored the differences in bile acid metabolism between infants and adults
Impact:
Microdosing and AMS can be used to generate usable PK data in infants. Research using the PhysioPD Platform identified mechanistic hypotheses for the causes of the PK variability.
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