A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice

Abstract

Background: The yeast-like fungi Pneumocystis, resides in lung alveoli and can cause a lethal infection known as Pneumocystis pneumonia (PCP) in hosts with impaired immune systems. Current therapies for PCP, such as trimethoprim-sulfamethoxazole (TMP-SMX), suffer from significant treatment failures and a multitude of serious side effects. Novel therapeutic approaches (i.e. newly developed drugs or novel combinations of available drugs) are needed to treat this potentially lethal opportunistic infection. Quantitative Systems Pharmacological (QSP) models promise to aid in the development of novel therapies by integrating available pharmacokinetic (PK) and pharmacodynamic (PD) knowledge to predict the effects of new treatment regimens. Results: In this work, we constructed and independently validated PK modules of a number of drugs with available pharmacokinetic data. Characterized by simple structures and well constrained parameters, these PK modules could serve as a convenient tool to summarize and predict pharmacokinetic profiles. With the currently accepted hypotheses on the life stages of Pneumocystis, we also constructed a PD module to describe the proliferation, transformation, and death of Pneumocystis. By integrating the PK module and the PD module, the QSP model was constrained with observed levels of asci and trophic forms following treatments with multiple drugs. Furthermore, the temporal dynamics of the QSP model were validated with corresponding data. Conclusions: We developed and validated a QSP model that integrates available data and promises to facilitate the design of future therapies against PCP.