A team of researchers in the University of Cincinnati (UC) College of Medicine has developed a quantitative systems pharmacology (QSP) approach, which uses computational models to predict interactions between a drug and its impact on the body’s biological systems and disease agents, to develop new treatments for Pneumocystis pneumonia, a lethal infection in immunosuppressed patients.
"QSP models promise to aid in the development of novel therapies by integrating pharmacokinetic (PK) and pharmacodynamics (PD) data and knowledge on biological systems to predict the effects of new treatment regimens,” explains Tongli Zhang, PhD, an assistant professor in the Department of Pharmacology and Systems Physiology, and the study’s corresponding author.
Richard Ballweg, a PhD candidate, in the Department of Pharmacology and Systems Physiology, is first author on the study.
Pneumocystis pneumonia (PCP) is a cause of morbidity in HIV-positive patients and in other patients undergoing therapy that suppress the body’s immune system. Even with the introduction of highly active anti-retroviral therapy, PCP still causes death in about 15 percent of all HIV-infected patients.
Researchers constructed and independently validated PK (Pharmacokinetics) modules that describe the distribution and decay of four drugs: three from the antifungal echinocandin family—anidulafungin, caspofungin and micafungin—and a fourth drug, trimethoprim-sulfamethoxazole, with available pharmacokinetic data collected in animal models, says Melanie Cushion, PhD, senior associate dean for research in the College of Medicine and a study co-author.
"Characterized by simple structure and well-constrained parameters, these PK modules could serve as a convenient tool to summarize and predict pharmacokinetic profiles,” says Cushion, also professor in the Division of Infectious Diseases.
Researchers used currently accepted hypotheses on the life cycle stages of Pneumocystis to also construct a PD (Pharmacodynamics) module to describe the proliferation, replication modes, slow decay in absence of drugs, and enhanced death in response to drugs by the pathogen Pneumocystis, explains Cushion.
After integrating the PK module and PD module, the QSP model was further constrained with observed levels of asci and trophic forms (life cycle stages) of Pneumocystis following treatments with multiple drugs. The temporal dynamics of the QSP model were validated with corresponding data, says Cushion.
"Pneumocystis pneumonia has two very different life cycle stages,” explains Cushion. "With the drugs that we modeled which are the echinocandins, they target only one form—the asci—and they disappear pretty quickly, but what is interesting is the other form, the trophic forms, remain in the lungs. They decrease a bit but maintain stable numbers while under treatment with the echinocandins.
"If you take the drug away the asci return and increase in number and the trophic forms begin to replicate,” Cushion continues. "What we are trying to do is understand how we could use those concepts for a new type of therapeutic approach.”
"What is relevant here is our model can be adapted to other infectious agents,” says Cushion. "Now that we understand the life cycle of Pneumocystis, we can model the impact of new drugs that are coming out for Pneumocystis treatment as well as for other fungal infections. One of the problems with Pneumocystis pneumonia is there are few drugs with which to treat it. The gold standard is trimethoprim-sulfamethoxazole (TMP-SMX), but this combination exerts many side effects. Fifty percent of AIDS patients cannot tolerate TMP-SMX treatment and must be switched to lesser effective therapies.
"That’s why it is important to understand what these drugs do to the individual life cycle stages of Pneumocystis. The residual organisms that remain behind after treatment can repopulate and cause pneumonia after the drug is stopped, suggesting the quiescence may be a survival mechanism. These fungi have been around for a very long time and they collaborate with the host that they inhabit for survival. They prefer to maintain a balance without killing their hosts, but once the host upsets this balance with a compromised immune system, the fungi take advantage and proliferate.”
Cushion says the QSP model is a transdisciplinary effort that brings two very diverse disciplines together to create something new.
Others participating in the study include Guan-Sheng Liu, PhD, a former postdoctoral fellow,
Alan Ashbaugh, Yin Zhang, and Joseph Facciolo.
The study was funded by institutional support from the University of Cincinnati and funding from the U.S. Department of Veterans Affairs.