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Mathematical biology and pharmacology models have a long and rich history in the fields of medicine and physiology, impacting our understanding of disease mechanisms and the development of novel therapeutics. With an increased focus on the pharmacology application of system models and the advances in data science spanning mechanistic and empirical approaches, there is a significant opportunity and promise to leverage these advancements to enhance the development and application of the systems pharmacology field. In this paper, we will review milestones in the evolution of mathematical biology and pharmacology models, highlight some of the gaps and challenges in developing and applying systems pharmacology models, and provide a vision for an integrated strategy that leverages advances in adjacent fields to overcome these challenges. [ABSTRACT FROM AUTHOR]

Gaucher's disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first‐line SRT approved for GD1, on treatment‐naïve or patients with ERT‐stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype‐phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics. [ABSTRACT FROM AUTHOR]