Predicting the impact of infectious diarrhea pathophysiology on drug disposition

Abstract

In the field of global health, physiologically based pharmacokinetic (PBPK) modeling has improved the confidence in malaria and tuberculosis (TB) drug development programs by assisting with first in human dose predictions, assessing potential drug‐drug interactions, and designing efficacious dosing regimens. PBPK models are composed of a compound file and a virtual physiology/population, and the impact of PBPK modeling in malaria and TB research is largely based on the substantial effort to improve both components. For example, compound files for commonly used therapeutics in malaria and TB have been developed through initiatives led by Medicines for Malaria Venture (MMV) and the Critical Path to TB Drug Regimens (CPTR). In addition, there has been considerable effort to develop virtual populations for these disease areas. Specifically, the focus of physiology and population model development for malaria has been on pediatric and pregnancy models. For TB, a virtual South African population has been generated which captures relevant genetic variants and TB‐related physiological changes that affect drug distribution and metabolism in this population.While the successful application of PBPK modeling in malaria and TB drug development has demonstrated the usefulness of this approach in global health, PBPK modeling has not been extensively applied to the area of drug development for enteric pathogens. In 2015, diarrhea caused > 688 million illnesses in children under 5 and was a leading cause of death among all ages (>1.3 million deaths). Despite advances in both the development of vaccines and small molecule therapeutics, new treatments are urgently needed for the treatment of multi drug resistant (MDR) bacterial pathogens and disease areas without an efficacious vaccine treatment. In symptomatic patients, we expect diarrhea to be associated with a reduction in gastrointestinal (GI) transit times, altered luminal pH, increased luminal volume, and disrupted epithelial integrity. However, the extent of these changes is often not clear. In addition, there has been insufficient clinical data to support how the pathophysiology may impact therapeutic disposition. To initially address this lack of clinical data, an aim of a recently completed clinical study in Malawi (NCT03341767) was to characterize the PK of clofazimine in HIV+ adult populations divided into two groups (diarrhea vs. non‐diarrheal). These clinical data were used to inform PBPK modeling efforts to predict the impact of diarrhea on clofazimine disposition and to relate the clinical study PK and efficacy outcomes to those obtained with pre‐clinical animal models of disease. While this work primarily focused on participants with cryptosporidiosis, our results provide a foundation for future efforts to use PBPK models in the development of therapeutics intended for various study populations with diarrhea.Support or Funding InformationBill and Melinda Gates Foundation Award OPP1172544